SU\G(𝔸)/K·U
Sign Up for free Log In
Biochemistry, Genetics and Molecular Biology › Molecular Biology

Melanoma and MAPK Pathways

Works Count: 39239

Description

This cluster of papers focuses on the mammalian MAP kinase signaling pathways, particularly their role in cancer, with a specific emphasis on melanoma. It covers the genetic mutations, targeted therapies, resistance mechanisms, and the impact of MAP kinase pathways on cell proliferation and immune response.

Keywords

MAP Kinase; BRAF gene; Melanoma; Signal Transduction; ERK pathway; Cancer Therapy; MEK Inhibition; Cell Proliferation; Oncogenic Mutations; Immune Response

The mitogen-activated protein kinase signal transduction pathway

1993-07-01
Roger J. Davis

Molecular classification of cutaneous malignant melanoma by gene expression profiling

2000-08-01
Michael Bittner , P.S. Meltzer , Yaning Chen +7 more
View PDF Chat

Genomic Classification of Cutaneous Melanoma

2015-06-01
Rehan Akbani , Kadir C. Akdemir , Bülent Arman Aksoy +7 more
View PDF Chat

Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib

2014-11-16
Caroline Robert , Bogusława Karaszewska , Jacob Schachter +7 more
The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor … The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).
View PDF Chat

A synthetic inhibitor of the mitogen-activated protein kinase cascade.

1995-08-15
David T. Dudley , Long Pang , Stuart J. Decker +2 more
Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We … Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.
View PDF Chat

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

2010-09-01
Gideon Bollag , Peter Hirth , James Tsai +7 more
View PDF Chat

JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain

1994-03-01
Benoit Dérijard , Masahiko Hibi , I‐Huan Wu +5 more

Skepinone-L, a Novel Potent and Highly Selective Inhibitor of p38 MAP Kinase, Effectively Impairs Platelet Activation and Thrombus Formation

2013-01-01
Oliver Borst , Britta Walker , Patrick Münzer +7 more
Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of … Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of skepinone-L, which is, to our knowledge, the first ATP-competitive p38 MAPK inhibitor with excellent in vivo efficacy and selectivity. Therefore, skepinone-L is a valuable probe for chemical biology research, and it may foster the development of a unique class of kinase inhibitors.
View PDF Chat

Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells

1994-06-17
Sally A. Cowley

Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions*

2001-04-01
Gray W. Pearson , Fred L. Robinson , Tara Beers Gibson +4 more
Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental … Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms. MAP kinases lie in protein kinase cascades. This review discusses the regulation and functions of mammalian MAP kinases. Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted. Particular emphasis is on ERK1/2.
View PDF Chat

Mammalian MAP kinase signalling cascades

2001-03-01
Lufen Chang , Michael Karin

A MAP Kinase Targeted by Endotoxin and Hyperosmolarity in Mammalian Cells

1994-08-05
Jiahuai Han , Jeffrey Lee , L. Bibbs +1 more
Mammalian cells respond to endotoxic lipopolysaccharide (LPS) by activation of protein kinase cascades that lead to new gene expression. A protein kinase, p38, that was tyrosine phosphorylated in response to … Mammalian cells respond to endotoxic lipopolysaccharide (LPS) by activation of protein kinase cascades that lead to new gene expression. A protein kinase, p38, that was tyrosine phosphorylated in response to LPS, was cloned. The p38 enzyme and the product of the Saccharomyces cerevisiae HOG1 gene, which are both members of the mitogen-activated protein (MAP) kinase family, have sequences at and adjacent to critical phosphorylation sites that distinguish these proteins from most other MAP kinase family members. Both HOG1 and p38 are tyrosine phosphorylated after extracellular changes in osmolarity. These findings link a signaling pathway in mammalian cells with a pathway in yeast that is responsive to physiological stress.

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

2010-02-23
Poulikos I. Poulikakos , Chao Zhang , Gideon Bollag +2 more
View PDF Chat

Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine

1995-03-01
Joël Raingeaud , Shashi Kumar Gupta , Jeffrey S. Rogers +4 more
Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERK group regulates multiple targets in response … Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERK group regulates multiple targets in response to growth factors via a Ras-dependent mechanism. In contrast, JNK activates the transcription factor c-Jun in response to pro-inflammatory cytokines and exposure of cells to several forms of environmental stress. Recently, a novel mammalian protein kinase (p38) that shares sequence similarity with mitogen-activated protein (MAP) kinases was identified. Here, we demonstrate that p38, like JNK, is activated by treatment of cells with pro-inflammatory cytokines and environmental stress. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182. Immunofluorescence microscopy demonstrated that p38 MAP kinase is present in both the nucleus and cytoplasm of activated cells. Together, these data establish that p38 is a member of the mammalian MAP kinase group. Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERK group regulates multiple targets in response to growth factors via a Ras-dependent mechanism. In contrast, JNK activates the transcription factor c-Jun in response to pro-inflammatory cytokines and exposure of cells to several forms of environmental stress. Recently, a novel mammalian protein kinase (p38) that shares sequence similarity with mitogen-activated protein (MAP) kinases was identified. Here, we demonstrate that p38, like JNK, is activated by treatment of cells with pro-inflammatory cytokines and environmental stress. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182. Immunofluorescence microscopy demonstrated that p38 MAP kinase is present in both the nucleus and cytoplasm of activated cells. Together, these data establish that p38 is a member of the mammalian MAP kinase group.
View PDF Chat

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

2007-05-14
Patrick J. Roberts , Channing J. Der

SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1

1995-05-08
Ana Cuenda , J.B. Rouse , Yair N. Doza +5 more
A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739–746]. We now show that one of these compounds … A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739–746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (IC 50 = 0.6 μM), suppresses the activation of MAPKAP kinase‐2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin‐1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase‐2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase‐2 in vivo. The specificity of SB 203580 was indicated by its failure to inhibit 12 other protein kinases in vitro, and by its lack of effect on the activation of RK kinase and other MAP kinase cascades in vivo. We suggest that SB 203580 will be useful for identifying other physiological roles and targets of RK and MAPKAP kinase‐2.

Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

2010-11-24
Ramin Nazarian , Hubing Shi , Qi Wang +7 more

Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling Pathways

1997-01-03
Hidenori Ichijo , Eisuke Nishida , Kenji Irie +7 more
Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that … Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-α (TNF-α). Moreover, TNF-α-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.

PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in Vivo

1995-11-01
Dario R. Alessi , Ana Cuenda , Philip Cohen +2 more
PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of constitutive activity (Dudley, D. … PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R.(1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7686-7689). Here we report that PD 098059 does not inhibit Raf-activated MAPKK1 but that it prevents the activation of MAPKK1 by Raf or MEK kinase in vitro at concentrations (IC50 = 2-7 μM) similar to those concentrations that inhibit dephosphorylated MAPKK1 or MAPKK1(S217E,S221E). PD 098059 inhibited the activation of MAPKK2 by Raf with a much higher IC50 value (50 μM) and did not inhibit the phosphorylation of other Raf or MEK kinase substrates, indicating that it exerts its effect by binding to the inactive form of MAPKK1. PD 098059 also acts as a specific inhibitor of the activation of MAPKK in Swiss 3T3 cells, suppressing by 80-90% its activation by a variety of agonists. The high degree of specificity of PD 098059 in vitro and in vivo is indicated by its failure to inhibit 18 protein Ser/Thr kinases (including two other MAPKK homologues) in vitro by its failure to inhibit the in vivo activation of MAPKK and MAP kinase homologues that participate in stress and interleukin-1-stimulated kinase cascades in KB and PC12 cells, and by lack of inhibition of the activation of p70 S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells. PD 098059 (50 μM) inhibited the activation of p42MAPK and isoforms of MAP kinase-activated protein kinase-1 in Swiss 3T3 cells, but the extent of inhibition depended on how potently c-Raf and MAPKK were activated by any particular agonist and demonstrated the enormous amplification potential of this kinase cascade. PD 098059 not only failed to inhibit the activation of Raf by platelet-derived growth factor, serum, insulin, and phorbol esters in Swiss 3T3 cells but actually enhanced Raf activity. The rate of activation of Raf by platelet-derived growth factor was increased 3-fold, and the subsequent inactivation that occurred after 10 min was prevented. These results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway. PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R.(1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7686-7689). Here we report that PD 098059 does not inhibit Raf-activated MAPKK1 but that it prevents the activation of MAPKK1 by Raf or MEK kinase in vitro at concentrations (IC50 = 2-7 μM) similar to those concentrations that inhibit dephosphorylated MAPKK1 or MAPKK1(S217E,S221E). PD 098059 inhibited the activation of MAPKK2 by Raf with a much higher IC50 value (50 μM) and did not inhibit the phosphorylation of other Raf or MEK kinase substrates, indicating that it exerts its effect by binding to the inactive form of MAPKK1. PD 098059 also acts as a specific inhibitor of the activation of MAPKK in Swiss 3T3 cells, suppressing by 80-90% its activation by a variety of agonists. The high degree of specificity of PD 098059 in vitro and in vivo is indicated by its failure to inhibit 18 protein Ser/Thr kinases (including two other MAPKK homologues) in vitro by its failure to inhibit the in vivo activation of MAPKK and MAP kinase homologues that participate in stress and interleukin-1-stimulated kinase cascades in KB and PC12 cells, and by lack of inhibition of the activation of p70 S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells. PD 098059 (50 μM) inhibited the activation of p42MAPK and isoforms of MAP kinase-activated protein kinase-1 in Swiss 3T3 cells, but the extent of inhibition depended on how potently c-Raf and MAPKK were activated by any particular agonist and demonstrated the enormous amplification potential of this kinase cascade. PD 098059 not only failed to inhibit the activation of Raf by platelet-derived growth factor, serum, insulin, and phorbol esters in Swiss 3T3 cells but actually enhanced Raf activity. The rate of activation of Raf by platelet-derived growth factor was increased 3-fold, and the subsequent inactivation that occurred after 10 min was prevented. These results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway.
View PDF Chat

Specificity and mechanism of action of some commonly used protein kinase inhibitors

2000-10-01
Stephen Davies , Helen Reddy , Matilde Caivano +1 more
The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds … The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.
View PDF Chat

High frequency of BRAF mutations in nevi

2002-11-25
Pamela M. Pollock , Ursula L. Harper , Katherine Hansen +7 more

Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases

2002-12-05
Gary L. Johnson , Razvan Lapadat
Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which … Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.

MAP kinase signalling pathways in cancer

2007-05-14
Amardeep S. Dhillon , Suzanne Hagan , Oliver Rath +1 more

MAPK signal pathways in the regulation of cell proliferation in mammalian cells

2002-03-01
Wei Zhang , Hui-Tu Liu
View PDF Chat

Mammalian Ras interacts directly with the serine/threonine kinase raf

1993-07-01
Anne B. Vojtek , Stanley M. Hollenberg , Jonathan A. Cooper

How MAP Kinases Are Regulated

1995-06-01
Melanie H. Cobb , Elizabeth J. Goldsmith
The closely related MAP kinases,1(1) extracellular signal-regulated protein kinases 1 and 2 (ERK1 and ERK2), are ubiquitous components of signal transduction pathways. ERK1 and ERK2 are activated by diverse extracellular … The closely related MAP kinases,1(1) extracellular signal-regulated protein kinases 1 and 2 (ERK1 and ERK2), are ubiquitous components of signal transduction pathways. ERK1 and ERK2 are activated by diverse extracellular stimuli and by protooncogene products that induce proliferation or enhance differentiation (reviewed in Refs. 1 and 2). MAP kinase phosphorylations have an impact on processes in the cytoplasm, the nucleus, the cytoskeleton, and the membrane. The variety of signals that conscript the MAP kinase pathway demonstrates that this cascade serves a myriad of purposes, and the consequences of its activation will depend on cellular context.
View PDF Chat

Mitogen-activated protein kinase pathways

1997-04-01
Megan J. Robinson , Melanie H. Cobb

Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain.

1993-11-01
Masahiko Hibi , Anning Lin , Tod Smeal +2 more
The activity of c-Jun is regulated by phosphorylation. Various stimuli including transforming oncogenes and UV light, induce phosphorylation of serines 63 and 73 in the amino-terminal activation domain of c-Jun … The activity of c-Jun is regulated by phosphorylation. Various stimuli including transforming oncogenes and UV light, induce phosphorylation of serines 63 and 73 in the amino-terminal activation domain of c-Jun and thereby potentiate its trans-activation function. We identified a serine/threonine kinase whose activity is stimulated by the same signals that stimulate the amino-terminal phosphorylation of c-Jun. This novel c-Jun amino-terminal kinase (JNK), whose major form is 46 kD, binds to a specific region within the c-Jun trans-activation domain and phosphorylates serines 63 and 73. Phosphorylation results in dissociation of the c-Jun-JNK complex. Mutations that disrupt the kinase-binding site attenuate the response of c-Jun to Ha-Ras and UV. Therefore the binding of JNK to c-Jun is of regulatory importance and suggests a mechanism through which protein kinase cascades can specifically modulate the activity of distinct nuclear targets.
View PDF Chat

Signal integration by JNK and p38 MAPK pathways in cancer development

2009-07-24
Erwin F. Wagner , Ángel R. Nebreda

Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase

1998-07-01
Margaret Favata , Kurumi Y. Horiuchi , Elizabeth J. Manos +7 more
The compound U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene) was identified as an inhibitor of AP-1 transactivation in a cell-based reporter assay. U0126 was also shown to inhibit endogenous promoters containing AP-1 response elements but … The compound U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene) was identified as an inhibitor of AP-1 transactivation in a cell-based reporter assay. U0126 was also shown to inhibit endogenous promoters containing AP-1 response elements but did not affect genes lacking an AP-1 response element in their promoters. These effects of U0126 result from direct inhibition of the mitogen-activated protein kinase kinase family members, MEK-1 and MEK-2. Inhibition is selective for MEK-1 and -2, as U0126 shows little, if any, effect on the kinase activities of protein kinase C, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6, Cdk2, or Cdk4. Comparative kinetic analysis of U0126 and the MEK inhibitor PD098059 (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) <i>Proc. Natl. Acad. Sci U. S. A.</i>92, 7686–7689) demonstrates that U0126 and PD098059 are noncompetitive inhibitors with respect to both MEK substrates, ATP and ERK. We further demonstrate that the two compounds bind to ΔN3-S218E/S222D MEK in a mutually exclusive fashion, suggesting that they may share a common or overlapping binding site(s). Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for ΔN3-S218E/S222D MEK than does PD098059. We further tested the effects of these compounds on the activity of wild type MEK isolated after activation from stimulated cells. Surprisingly, we observe a significant diminution in affinity of both compounds for wild type MEK as compared with the ΔN3-S218E/S222D mutant enzyme. These results suggest that the affinity of both compounds is mediated by subtle conformational differences between the two activated MEK forms. The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for <i>in vitro</i> and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.
View PDF Chat

Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

2014-09-29
Georgina V. Long , Daniil Stroyakovskiy , Helen Gogas +7 more
Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K … Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.
View PDF Chat

SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

2001-11-20
Brydon L. Bennett , Dennis T. Sasaki , Brion W. Murray +7 more
Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an … Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 ( K i = 0.19 μM). SP600125 is a reversible ATP-competitive inhibitor with &gt;20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2 , IL-2 , IFN -γ, TNF -α, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-α and inhibited anti-CD3-induced apoptosis of CD4 + CD8 + thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
View PDF Chat

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

2010-08-25
Keith T. Flaherty , Igor Puzanov , Kevin B. Kim +7 more
The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.We … The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
View PDF Chat

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

2011-03-01
Marie Cargnello , Philippe P. Roux
SUMMARY The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate … SUMMARY The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.
View PDF Chat

Combined Vemurafenib and Cobimetinib in <i>BRAF</i>-Mutated Melanoma

2014-09-29
James Larkin , Paolo A. Ascierto , Brigitte Dréno +7 more
The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. … The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).
View PDF Chat

Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF

2004-03-01
Paul Wan , Mathew J. Garnett , S. Mark Roe +7 more
View PDF Chat

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

2011-06-05
Paul B. Chapman , Axel Hauschild , Caroline Robert +7 more
Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E … Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
View PDF Chat

A Landscape of Driver Mutations in Melanoma

2012-07-01
Eran Hodis , Ian R. Watson , Gregory V. Kryukov +7 more
View PDF Chat

Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma

2012-06-14
Keith T. Flaherty , Caroline Robert , Peter Hersey +7 more
Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often … Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.
View PDF Chat

CREB: A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals

1999-06-01
Adam J. Shaywitz , Michael E. Greenberg
▪ Abstract Extracellular stimuli elicit changes in gene expression in target cells by activating intracellular protein kinase cascades that phosphorylate transcription factors within the nucleus. One of the best characterized … ▪ Abstract Extracellular stimuli elicit changes in gene expression in target cells by activating intracellular protein kinase cascades that phosphorylate transcription factors within the nucleus. One of the best characterized stimulus-induced transcription factors, cyclic AMP response element (CRE) -binding protein (CREB), activates transcription of target genes in response to a diverse array of stimuli, including peptide hormones, growth factors, and neuronal activity, that activate a variety of protein kinases including protein kinase A (PKA), pp90 ribosomal S6 kinase (pp90RSK), and Ca2+/calmodulin-dependent protein kinases (CaMKs). These kinases all phosphorylate CREB at a particular residue, serine 133 (Ser133), and phosphorylation of Ser133 is required for CREB-mediated transcription. Despite this common feature, the mechanism by which CREB activates transcription varies depending on the stimulus. In some cases, signaling pathways target additional sites on CREB or proteins associated with CREB, permitting CREB to regulate distinct programs of gene expression under different conditions of stimulation. This review will discuss the molecular mechanisms by which Ser133--phosphorylated CREB activates transcription, intracellular signaling pathways that lead to phosphorylation of CREB at Ser133, and features of each signaling pathway that impart specificity at the level of CREB activation.

BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis

2004-10-01
Scott M. Wilhelm , Christopher Carter , LiYa Tang +7 more
The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the … The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

2004-06-01
Philippe P. Roux , John Blenis
SUMMARY Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, … SUMMARY Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.
View PDF Chat

Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance

2006-10-10
James A. McCubrey , Linda S. Steelman , William H. Chappell +7 more
View PDF Chat

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

2012-10-01
Keith T. Flaherty , J. Infante , Adil Daud +7 more
Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial … Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.
View PDF Chat

Mutations of the BRAF gene in human cancer

2002-06-01
Helen Davies , Graham R. Bignell , Charles Cox +7 more
View PDF Chat

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

2012-06-25
Axel Hauschild , Jean‐Jacques Grob , Lev Demidov +7 more

Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib

2012-02-22
Jeffrey A. Sosman , Kevin B. Kim , Lynn M. Schuchter +7 more
Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant … Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial.
View PDF Chat

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma

2016-03-01
Willy Hugo , Jesse M. Zaretsky , Lu Sun +7 more
View PDF Chat

Specificity and mechanism of action of some commonly used protein kinase inhibitors

2000-09-26
Stephen Davies , Helen Reddy , Matilde Caivano +1 more
The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds … The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

The MAPK signaling cascade

1995-06-01
Rony Seger , Edwin G. Krebs
The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories … The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit autogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action of most, if not all, nonnuclear oncogenes. The pattern of MAPK cascade is not restricted to growth factor signaling and it is now known that signaling pathways initiated by phorbol esters, iono-phors, heat shock, and liganda for seven transmembrane receptors use distinct MAPK cascades with little or no cross-reactivity between them. In this review we emphasize primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describe their involvement in different cellular processes.—Seger, R., Krebs, E. G. The MAPK signaling cascade. FASEB J. 9, 726-735 (1995)

Erratum: Randomized, Open-Label, Phase III Study of Tilsotolimod in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced Refractory Melanoma (ILLUMINATE-301)

2025-06-25
Adi Diab , Paolo A. Ascierto , Michele Maio +7 more | Journal of Clinical Oncology

A Stranger in the Slide: A Rare Collision of a Spitz Melanocytoma With a Novel MYH9::LTK Fusion and a Common BRAF Mutated Nevus Mimicking a Melanoma With a Preexistent Nevus

2025-06-25
Puk R. Meijs-Hermanns , Juliette M. J. Spitzer-Naaijkens , Lennart Kester +2 more | American Journal of Dermatopathology
Abstract: In this case report, we present a rare collision tumor consisting of a Spitz melanocytoma with a novel MYH9::LTK fusion, and a BRAFV600E mutated common dermal nevus in a … Abstract: In this case report, we present a rare collision tumor consisting of a Spitz melanocytoma with a novel MYH9::LTK fusion, and a BRAFV600E mutated common dermal nevus in a 25-year-old man. Based on morphology alone, the lesion could easily have been misdiagnosed as a melanoma with a preexisting nevus. However, only the common dermal nevus showed BRAFV600E expression on immunohistochemical analysis, pointing toward the possibility of a collision tumor and guiding further molecular analyses. Although MYH9::LTK fusions have not been previously described in Spitz tumors, we classified this lesion as Spitz based on the epithelioid morphology and kinase fusion driver. Because there was dermal mitotic activity and heterozygous CDKN2A loss, we signed this lesion out as Spitz melanocytoma, in association with an unrelated BRAFV600E mutated dermal nevus. This case underscores the relevance of performing immunohistochemistry and if needed additional molecular analyses to confirm the lineage and dignity of an atypical melanocytic lesion, in which a Spitz tumor is a diagnostic consideration, to prevent misdiagnosis.

Characterization of the BRAF interactome identifies BRAFV600E&lt;=&gt;TP53 interaction in melanoma

2025-06-25
Kayla O’Toole , Antonio Bascones Martínez , Brandon Murphy +7 more | bioRxiv (Cold Spring Harbor Laboratory)
Melanoma is a highly aggressive and frequently metastatic cancer with its incidence reported to be on the rise. Although most oncogenic drivers in melanoma converge on activation of the RAS&gt;RAF&gt;MEK&gt;ERK … Melanoma is a highly aggressive and frequently metastatic cancer with its incidence reported to be on the rise. Although most oncogenic drivers in melanoma converge on activation of the RAS&gt;RAF&gt;MEK&gt;ERK MAPK signaling pathway, not all MAPK-activating mutations are recurrently observed in this disease, suggesting a unique functional role for BRAFV600E, which is present in ~50% of all melanoma cases. However, the prevalence of BRAFV600E alterations over other known MAPK-promoting oncoproteins raises questions regarding whether BRAFV600E possesses additional functions outside of MAPK pathway activation. Thus, we performed TurboID to differentiate the interactome between wild-type BRAF and BRAFV600E. We identified novel interacting partners of normal vs. BRAFV600E, most strikingly being the tumor suppressor TP53. While TP53 is commonly altered or lost across many malignancies, it is notable that TP53 alterations are rare in melanoma. Our studies suggest that BRAFV600E can interact with and inactivate TP53, thus providing potential mechanistic explanation as to why TP53 inactivation or loss is infrequent in BRAFV600E-driven melanoma.

Receptor tyrosine kinase inhibitor tivozanib regulates cell state plasticity and restores MITF dependency in BRAF wild-type melanoma

2025-06-23
Yanni Ma , Xuhui Ma , Mei-Ling Hao +7 more | Acta Pharmacologica Sinica

Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies

2025-06-23
Yonghyo Kim , Viktória Doma , Uğur Çakır +7 more | Cancer
Abstract Background Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged … Abstract Background Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities. Methods Quantitative proteomics was performed on 151 melanoma‐related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation using mitochondrial inhibitors were conducted to evaluate therapeutic potential. Results Mitochondrial translation and oxidative phosphorylation (OXPHOS) were significantly upregulated in aggressive melanomas, particularly in BRAF‐mutant and metastatic tumors. Inhibition of mitochondrial pathways using antibiotics (doxycycline, tigecycline, and azithromycin) and OXPHOS inhibitors (VLX600, IACS‐010759, and BAY 87‐2243) demonstrated dose‐dependent antiproliferative effects in melanoma cell lines, sparing noncancerous melanocytes. These treatments disrupted mitochondrial function, suppressed key metabolic pathways, and induced apoptosis, highlighting the clinical relevance of targeting these pathways. Conclusions This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes.

The Evaluation of Potential Anticancer Activity of Meloxicam—In Vitro Study on Amelanotic and Melanotic Melanoma

2025-06-22
Marta Karkoszka-Stanowska , Zuzanna Rzepka , Dorota Wrześniok | International Journal of Molecular Sciences
Meloxicam (MLX), a member of the non-steroidal anti-inflammatory drugs (NSAIDs), is a preferential inhibitor of cyclooxygenase-2 (COX-2) responsible for the synthesis of pro-inflammatory prostaglandins. MLX, due to its inhibition of … Meloxicam (MLX), a member of the non-steroidal anti-inflammatory drugs (NSAIDs), is a preferential inhibitor of cyclooxygenase-2 (COX-2) responsible for the synthesis of pro-inflammatory prostaglandins. MLX, due to its inhibition of the COX-2 enzyme, which is overexpressed in many cancers, including melanoma, leading to rapid growth, angiogenesis, and metastasis, represents a potentially important compound with anticancer activity. This study aimed to investigate the potential anticancer activity of meloxicam against amelanotic C32 and melanotic COLO 829 melanoma cell lines. The objective was achieved by assessing cell metabolic activity using the WST-1 assay and analyzing mitochondrial potential, levels of reduced thiols, annexin, and caspases 3/7, 8, and 9 by imaging cytometry, as well as assessing reactive oxygen species (ROS) levels using the H2DCFDA probe. The amelanotic melanoma C32 was more sensitive to MLX exposure, thus exhibiting antiproliferative effects, a disruption of redox homeostasis, a reduction in mitochondrial potential, and an induction of apoptosis. The results provide robust molecular evidence supporting the pharmacological effects of MLX, highlighting its potential as a valuable agent for in vivo melanoma treatment.

Anticancer Quinolinol Small Molecules Target Multiple Pathways to Promote Cell Death and Eliminate Melanoma Cells Resistant to BRAF Inhibitors

2025-06-22
Xinjiang Wang , Rati Lama , Alexis D. Kelleher +7 more | Molecules
Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified … Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified using an MDM2-MDM4 E3 ligase-based high throughput screen and a cell-death-based secondary screen. Our previous studies showed that MMRi62 promotes MDM4 degradation in cells and induces p53-independent apoptosis in cancer cells. However, MMRi62 activity in solid tumor cells such as melanoma cells, especially in BRAF inhibitor resistant melanoma cells, have not been explored. Although its promotion of MDM4 degradation is clear, the direct MMRi62 targets in cells are unknown. In this report, we show that MMRi62 is a much more potent p53-independent apoptosis inducer than conventional MDM2 inhibitors in melanoma cells. A brief structure-activity study led to development of SC-62-1 with improved activity. SC-62-1 potently inhibits and eliminates clonogenic growth of melanoma cells that acquired resistance to BRAF inhibitors. We developed a pair of active and inactive SC-62-1 probes and profiled the cellular targets of SC-62-1 using a chemical biology approach coupled with IonStar/nano-LC/MS analysis. We found that SC-62-1 covalently binds to more than 15 hundred proteins in cells. Pathways analysis showed that SC-62-1 significantly altered several pathways including carbon metabolism, RNA metabolism, amino acid metabolism, translation and cellular response to stress. This study provides mechanistic insights into the mechanisms of action for MMRi62-like quinolinols. This study also suggests multi-targeting compounds like SC-62-1 might be useful for overcoming resistance to BRAF inhibitors for improved melanoma treatment.

Case report: Successful use of MEK inhibitors as an adjuvant approach in the treatment of pediatric MAP4-RAF1 fusion-positive solid tumor

2025-06-21
Yang Shen , Shixuan Zhang , Jiarong Wang +7 more | npj Precision Oncology
RAF protein kinase acts downstream of RAS in the MAPK pathway, and mutations in the RAF family protein BRAF are frequently observed in adult tumours, with MEK inhibitors proving effective … RAF protein kinase acts downstream of RAS in the MAPK pathway, and mutations in the RAF family protein BRAF are frequently observed in adult tumours, with MEK inhibitors proving effective in treatment. However, RAF family protein RAF1 fusions are rare, particularly in pediatric soft tissue tumors, and the efficacy of targeted therapies remains uncertain. This study presents a rare case of a MAP4-RAF1 fusion-positive solid tumor in a child, unresponsive to conventional chemotherapy, surgery, second-line chemotherapy, and sorafenib-targeted therapy. Protein structure simulations predicted trametinib to exhibit optimal efficacy among MEK inhibitors in structural modelling, and it then demonstrated clinical effectiveness in this child. This study underscores the importance of molecular interaction simulations in precise drug screening for clinical decision-making and highlights MEK inhibitors' potential as adjunctive therapy for pediatric RAF1 fusion tumors.

Do BRAF-targeted therapies have a role in the era of immunotherapy?

2025-06-20
Jorja Braden , Jordan W. Conway , J.S. Wilmott +3 more | ESMO Open

Tyrosine-Mediated Static and Dynamic Quenching of a Receptor Tyrosine Kinase Biosensor Reveals Inhibitor Binding Modes and Kinase Conformations

2025-06-19
Zachary D. Baker , Andrew R. Thompson , David D. Thomas +1 more | ACS Chemical Biology
Conformational changes triggered by kinase inhibitors are a major factor driving specificity and efficacy, but few scalable methods exist for differentiating induced conformations and binding modes. Using the receptor tyrosine … Conformational changes triggered by kinase inhibitors are a major factor driving specificity and efficacy, but few scalable methods exist for differentiating induced conformations and binding modes. Using the receptor tyrosine kinase MET, we show that three classes of inhibitors can be distinguished by their contrasting effects on static and dynamic quenching of a fluorescent dye attached to the activation loop. Quenching is mediated by tyrosine residues on the flexible activation loop, and inhibitor binding induces order in the loop, sequestering the tyrosines and differentially suppressing static and dynamic quenching in a manner that is dependent on the induced structural state. Type I MET inhibitors have a large static and moderate dynamic component, type II inhibitors have only a static component, and active-state-selective inhibitors relieve both components to similar extents. These distinct dequenching signatures allow the straightforward detection of each binding mode by using parallel steady-state and time-resolved fluorescence measurements. We show that this technique can be applied to rapidly assess the effects of resistance mutations on inhibitor binding and can report on the chemical interactions and conformational changes that drive these effects. Conservation of the three activation loop tyrosine residues across many receptor tyrosine kinases suggests that this approach has broad utility.

Design, synthesis, and biological evaluation of JNK1 peptide inhibitors for alleviating insulin resistance in type 2 diabetes

2025-06-19
Heng Cai , Yuting Wang , Hong Jiang +5 more | European Journal of Medicinal Chemistry

Poor Diagnostic Performance of the Melanin-Binding Tracer [18 F]MEL050 in Human Melanoma Indicates Biological Heterogeneity

2025-06-19
Robert E. Ware , Damien Kee , Peter Roselt +7 more | Molecular Imaging and Biology
Abstract Purpose Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is … Abstract Purpose Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is expressed in few other tissues. Following preclinical evaluation of the melanin-targeting PET tracer, [18F]-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide ([18F]MEL050), we sought to evaluate this agent in patients with melanoma. Method A phase I clinical trial was performed in ten patients with metastatic melanoma. Safety, dosimetry and diagnostic performance of intravenously administered][18F]MEL050 were evaluated. Based on results from this trial, we further assessed the prevalence and prognostic significance of loss of melanin expression in two historical patient cohorts for which there were matching histological and clinical outcome data. Results Across the trial cohort, no adverse safety signals resulted from [18F]MEL050 administration. The whole-body effective dose was 0.0163 mSV/MBq for an adult male and 0.0206 mSV/MBq for an adult female. The human biodistribution was favorable with low uptake in organs at high risk of metastatic spread, including the brain. Of metastatic sites identified as melanoma on [18F]FDG PET/CT, only 31/65 (48%) were positive on [18F]MEL050 PET. Four [18F]FDG+[18F]MEL050+ metastases were resected from three patients and found to be melanotic by histological examination, whereas five [18F]FDG+[18F]MEL050- metastases from two patients were amelanotic. In our historical cohorts, amelanosis was more common in metastatic than primary disease (45% versus 20%) and the presence of melanin within sentinel lymph node metastases was associated with worse disease-free (HR 2.3 95% CI 1.3 - 4.3, p = 0.002) and disease-specific survivals (HR 3.6, 95% CI 1.4 - 9.7, p = 0.009) in stage III disease, compared with amelanotic sentinel lymph node metastases. Conclusion We propose caution in the use of melanin-targeted agents for melanoma diagnosis and therapy until their utility as prognostic or predictive imaging biomarkers, and the biological implications of loss of melanin deposition during melanoma progression, are better understood.

Melanoma update: is a cure now in sight?

2025-06-19
Samrin Liaqat , Muhammad Adnan Khattak | Internal Medicine Journal
Abstract Melanoma, one of the most aggressive skin cancers, poses a significant global health concern due to its high metastatic potential and resistance to conventional treatments. This review explores recent … Abstract Melanoma, one of the most aggressive skin cancers, poses a significant global health concern due to its high metastatic potential and resistance to conventional treatments. This review explores recent advancements in melanoma treatment, particularly the impact of targeted therapies and immunotherapies which have significantly extended survival and improved the quality of life for advanced melanoma patients. Additionally, the innovative combination and sequential strategies, with immune checkpoint inhibitors and cancer vaccines or targeted therapies against BRAF mutations, mark a promising direction. Recent advances in tumour infiltrating lymphocytes and oncolytic virus therapy and personalised cancer vaccine development are also covered, highlighting the role of precision medicine in achieving tailored, effective treatments. Despite these advancements, challenges persist, including drug resistance and the need for reliable biomarkers to predict treatment response and select patients. This review underscores the ongoing efforts in research and clinical trials to refine therapeutic strategies, improve treatment outcomes for a larger population detection and, ultimately, advance towards a cure for melanoma.

Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice

2025-06-18
Pratima Nangia‐Makker , Madison Ahrens , Neeraja Purandare +6 more | Cells
Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies … Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine how vemurafenib endurance levels drive metabolic plasticity, we developed isogenic BRAFV600E VemR melanoma models with variant vemurafenib tolerances and performed an integrative analysis of metabolomic and transcriptome alterations using metabolome, Mitoplate-S1, Seahorse, and RNA-seq assays. Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. β-catenin, MITF, and ABCB5 levels are upregulated in both VemR models, and ICG-001 treatment restored vemurafenib sensitivity with reductions in MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration. Whereas β-catenin signaling induced TCA cycle and OXPHOS in highly drug tolerant A2058VemR cells, it activated pentose phosphate pathway in M14VemR cells with low vemurafenib tolerance, both of which are inhibited by ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies.

Durable complete response in a patient with BRAF-mutated advanced melanoma with ocular and skin toxicities from BRAF/MEK targeted therapy after immune checkpoint inhibitor treatment: a case report

2025-06-17
Carlotta Bertolina , Marinella Bertolotti , C Leporati +5 more | Dermatology Reports
Here we report the case of a woman suffering from advanced melanoma who developed severe toxicities with BRAF and MEK inhibitors (BRAFis, MEKis), given as second-line therapy after failure of … Here we report the case of a woman suffering from advanced melanoma who developed severe toxicities with BRAF and MEK inhibitors (BRAFis, MEKis), given as second-line therapy after failure of immunotherapy, who achieved a complete and durable response lasting for over 5 years. Significant progress has been achieved in the treatment of advanced melanoma with immune checkpoint inhibitors (ICIs) and targeted therapies using BRAFis and MEKis. While these treatments improve survival, they also pose risks of severe toxicities. Notably, when targeted therapy follows immunotherapy, immune-mediated toxicities may emerge months later due to tumor microenvironment modulation. Despite these risks, both approaches offer a durable response in eligible patients. Further understanding is needed to determine how prior immunotherapy may influence subsequent toxicity risks of target therapy. Understanding these factors could optimize treatment strategies and improve patient outcomes.

Novel dibenzoylmethane derivative 2-allyl-1,3-diphenyl-1,3-propanedione: a safe and effective topical treatment for melanoma

2025-06-17
Jefferson Viktor de Paula Barros Baêta , Mariá Aparecida Braga Rocha e Oliveira , Flaviane Ribeiro Nascimento +6 more | Anti-Cancer Drugs
This study investigated 2-allyl-1,3-diphenyl-1,3-propanedione (DPAP), a dibenzoylmethane derivative, as a potentially more effective and safer alternative to dacarbazine for melanoma treatment. The antitumor activity of DPAP was assessed through comprehensive … This study investigated 2-allyl-1,3-diphenyl-1,3-propanedione (DPAP), a dibenzoylmethane derivative, as a potentially more effective and safer alternative to dacarbazine for melanoma treatment. The antitumor activity of DPAP was assessed through comprehensive in-vitro, in-silico, and in-vivo experiments. In-vitro assays evaluated DPAP’s IC 50 values against melanoma cells, benchmarking its efficacy against dacarbazine. Molecular analyses explored apoptosis mechanisms, emphasizing the roles of FAS receptors and caspase pathways. In-silico absorption, distribution, metabolism, excretion, and toxicity analysis provided insights into DPAP’s pharmacokinetic profile, including absorption, distribution, metabolism, and toxicity. In-vivo studies examined its effects on tumor volume, vascular endothelial growth factor (VEGF) levels, and the histopathology of the liver, kidney, and lymph nodes. DPAP demonstrated significantly enhanced antitumor activity, reflected by markedly lower IC 50 values compared with dacarbazine, underscoring its superior efficacy and specificity toward tumor cells. Molecular assays confirmed that DPAP induces apoptosis through modulation of FAS receptors and activation of caspase pathways. In-silico results revealed favorable pharmacokinetic properties, including high intestinal absorption and good tissue distribution, with no evidence of carcinogenic potential. Notably, in-vivo experiments showed that DPAP effectively reduced tumor volume and VEGF levels, while also preventing hepatotoxicity and nephrotoxicity. In addition, it inhibited the migration of tumor cells to lymph nodes. These findings position DPAP as a promising candidate for melanoma treatment, particularly as a topical therapeutic, offering enhanced efficacy and safety compared with existing treatments. DPAP is a promising candidate for melanoma treatment, particularly through topical application, offering a safer and more effective alternative to current treatments.

Targeting S-Nitrosylation to Overcome Therapeutic Resistance in NRAS-Driven Melanoma

2025-06-17
Jyoti Srivastava , Sanjay Premi | Cancers
NRAS-mutant melanoma represents a clinically challenging subset of melanoma with limited effective therapies and intrinsic resistance to targeted MEK inhibition. Recent findings highlight protein S-nitrosylation, a redox-dependent post-translational modification as … NRAS-mutant melanoma represents a clinically challenging subset of melanoma with limited effective therapies and intrinsic resistance to targeted MEK inhibition. Recent findings highlight protein S-nitrosylation, a redox-dependent post-translational modification as a critical modulator of MEK-ERK signaling and immune evasion in this context. In this commentary, we discuss how S-nitrosylation of MAPK components, including MEK and ERK, sustains oncogenic signaling and attenuates immunogenic cell death. Targeting this modification with nitric oxide synthase (NOS) inhibitors such as L-NAME, L-NMMA and 1400w restore sensitivity of MEK inhibitor, promotes dendritic cell activation, and enhances CD8+ T cell infiltration in preclinical models such as immunogenic mouse models and individual patient derived, primary melanoma cells. We also explore the emerging role of S-nitrosylation in regulating macrophage-mediated immune surveillance and propose translational strategies for combining redox modulation with targeted and immune therapies. These insights offer a compelling framework for overcoming therapeutic resistance and reprogramming the tumor immune microenvironment to activate the cytotoxic T-cells and enhance the responses to immunotherapy in NRAS-driven cancers.

NF-kB–p53 axis antagonism: A therapeutic opportunity in cancer treatment

2025-06-15
Ranjeet Kumar , D. C. Biswas | Indian Journal of Pathology and Oncology

MKK4 and MKK7 control degeneration of retinal ganglion cell somas and axons after glaucoma-relevant injury.

2025-06-13
Olivia J. Marola , Stephanie B. Syc‐Mazurek , S. Yablonski +3 more | Research Square (Research Square)
<title>Abstract</title> Glaucoma is characterized by programmed cell death of retinal ganglion cells (RGCs) after axonal injury. Several studies have shown the cell-intrinsic drivers of RGC degeneration act in a compartment-specific … <title>Abstract</title> Glaucoma is characterized by programmed cell death of retinal ganglion cells (RGCs) after axonal injury. Several studies have shown the cell-intrinsic drivers of RGC degeneration act in a compartment-specific manor. Recently, the transcription factors JUN and DDIT3 were identified as critical hubs regulating RGC somal loss after mechanical axonal injury. It is possible somal DDIT3 and JUN activity initiates axonal degeneration mechanisms in glaucoma. Alternatively, DDIT3 and JUN may act downstream of inciting degenerative mechanisms and only drive RGC somal loss. The MAP2Ks MKK4 and MKK7 control all JNK and JUN activity and can indirectly activate DDIT3. Furthermore, MKK4 and MKK7 have been shown to drive RGC axonal degeneration after mechanical axonal injury. The present work investigated whether JUN and DDIT3, or their upstream activators MKK4 and MKK7, control degeneration of RGC axons and somas after glaucoma-relevant injury. Ddit3 and Jun deletion did not prevent axonal degeneration in ocular hypertensive DBA/2J mice but prevented nearly all RGC somal loss. Despite robust somal survival, Ddit3 and Jun deletion did not preserve RGC somal viability (as assessed by PERG decline and soma shrinkage) in DBA/2J mice or after glaucoma-relevant mechanical axonal injury. In contrast, Mkk4 and Mkk7 deletion significantly lessened degeneration of RGC somas and axons, and preserved somal function and size after axonal injury. In summary, activation of MKK4 and MKK7 appears to be the inciting mechanism governing death of the entire RGC after glaucoma-relevant injury; driving death of the RGC soma (likely through activation of DDIT3 and JUN), decline in somal viability, and axonal degeneration via DDIT3 and JUN-independent mechanisms.

1996-LB: Icovamenib Rescues Human Myotube Atrophy Ex Vivo and Displays Complete Lean Mass Preservation in a Type 2 Diabetes Rat Model

2025-06-13
PRIYANKA SOMANATH , MINI BALAKRISHNAN , Thorsten Kirschberg +2 more | Diabetes
Introduction and Objective: GLP-1-based therapies have reported lean mass reductions of up to 40 to 60% of total weight loss in the clinic. Menin, a key regulator of beta cell … Introduction and Objective: GLP-1-based therapies have reported lean mass reductions of up to 40 to 60% of total weight loss in the clinic. Menin, a key regulator of beta cell mass, also modulates signaling pathways critical for muscle health. Menin-depleted mice display increased intercostal muscle mass and enhanced myogenesis. Icovamenib, an oral covalent menin inhibitor, enhanced response to GLP-1 therapies and beta cell proliferation in human islets and in a T2D rat model. The direct impact of icovamenib on myotube recovery and lean mass preservation was investigated. Methods: Ex-vivo derived 3D-engineered healthy human myotubes were cultured with icovamenib or garetosmab for 16 days, beginning one day prior to atrophy induction with Activin A or dexamethasone (dex), and myotube morphology was assessed. Additionally, Zucker diabetic fatty (ZDF) rats treated with icovamenib or vehicle for 14 days followed by 14 days with low dose semaglutide (sem) were examined for body composition parameters. Results: Icovamenib treatment resulted in a dose-dependent increase in healthy myotube length and width. Icovamenib protected against Activin A-induced myotube atrophy, displaying a pronounced increase in myotube width, outperforming the Activin A antagonist, garetosmab. Dex decreased myotube width, which was rescued by icovamenib. In the ZDF rat, icovamenib in combination with sem enhanced body weight reduction through selectively promoting fat loss vs. sem alone. Notably, combination-treated rats displayed a +12% change from baseline in the lean mass fraction (p=0.01), surpassing sem alone. Conclusion: Icovamenib enhanced healthy myotube morphology and promoted recovery from drug-induced atrophy ex vivo. In ZDF rats, combination of icovamenib and low dose sem induced greater body weight reduction with protected lean mass. Collectively, these results support combination of icovamenib with GLP-1RA based therapies as a promising strategy to enhance body weight reduction with preservation of muscle homeostasis. Disclosure P. Somanath: Employee; Biomea Fusion. M. Balakrishnan: None. T. Kirschberg: None. J.P. Frias: Employee; Biomea Fusion. Stock/Shareholder; Biomea Fusion. Board Member; T1D Exchange. Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Novo Nordisk, Sanofi. Research Support; Sanofi. Consultant; Sanofi. Speaker's Bureau; Sanofi. Research Support; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Consultant; Carmot Therapeutics, Inc, Altimmune Inc. Research Support; Altimmune Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc. Consultant; Pfizer Inc. Research Support; Merck &amp; Co., Inc. Consultant; Merck &amp; Co., Inc. Speaker's Bureau; Merck &amp; Co., Inc. Consultant; Akero Therapeutics, Inc. Research Support; Akero Therapeutics, Inc, 89bio, Inc. Consultant; 89bio, Inc. T. Butler: Employee; Biomea Fusion.

Differential expression gene screening and prognostic biomarkers of skin cutaneous melanoma based on GEPIA database

2025-06-13
Yu Zhang , Pingfang YAN , Gang Nie +1 more | Medical Research
[Objective] To explore the differential gene expression profiles between skin cutaneous melanoma (SKCM) and normal tissues using bioinformatics methods, and to evaluate their predictive value for patient survival and prognosis. … [Objective] To explore the differential gene expression profiles between skin cutaneous melanoma (SKCM) and normal tissues using bioinformatics methods, and to evaluate their predictive value for patient survival and prognosis. [Methods] Differentially expressed genes (DEGs) between tumor and normal tissues were identified using the GEPIA database. The correlation between key gene expression and overall survival was analyzed.[Results] A total of 6,457 significantly upregulated genes (FDR &lt; 0.05) were identified. The top 10 genes with the highest expression levels included PRAME, RP11-40C6.2, SERPINE2, SDC3, UBE2SP2, ETV5, PLOD3, EIF5AP4, UBE2S, and HNRNPCP2. Survival analysis revealed that the expression levels of EIF5AP4, UBE2S, and SERPINE2 were significantly associated with clinical prognosis. Specifically, high EIF5AP4 expression was significantly associated with shortened disease-free survival (DFS), while high UBE2S expression was significantly associated with reduced overall survival (OS) and DFS. In contrast, high SERPINE2 expression was significantly associated with prolonged OS and DFS.[Conclusion] This study suggests that UBE2S and EIF5AP4 may function as oncogenic factors promoting SKCM progression, whereas SERPINE2 may play a protective role. The combined expression of these three genes may serve as a novel molecular signature for prognostic evaluation in SKCM.

POLARIS: encorafenib plus binimetinib for people with BRAF V600-mutant melanoma with brain metastasis

2025-06-12
Alexander M. Menzies , Michael A. Davies | Future Oncology
POLARIS was a study to evaluate different doses of encorafenib plus binimetinib for people with BRAF V600-mutant melanoma with brain metastasis. The first part, known as the safety lead-in, looked … POLARIS was a study to evaluate different doses of encorafenib plus binimetinib for people with BRAF V600-mutant melanoma with brain metastasis. The first part, known as the safety lead-in, looked at a high dose of encorafenib (300 mg twice daily) combined with standard binimetinib (45 mg twice daily); in the phase 2 part, patients were given the standard dose of encorafenib (450 mg once daily) plus binimetinib. In the safety lead-in, many patients were unable to tolerate the high dose of encorafenib plus binimetinib. Despite recruitment challenges in POLARIS, in the 13 enrolled patients with unresectable metastatic BRAF V600-mutant melanoma with brain metastases, treatment with encorafenib plus binimetinib demonstrated intracranial activity, with a brain metastasis response rate of over 60%.

Multi-omics-based subtyping of melanoma suggests distinct immune and targeted therapy strategies

2025-06-12
Changchang Li , Xiaoqiong Lin , Jinhui Wang +3 more | Frontiers in Immunology
Background Melanoma is a highly heterogeneous malignancy with diverse molecular and clinical behaviors. A precise molecular classification is critical for improving prognostic assessment and guiding personalized therapy. Methods We performed … Background Melanoma is a highly heterogeneous malignancy with diverse molecular and clinical behaviors. A precise molecular classification is critical for improving prognostic assessment and guiding personalized therapy. Methods We performed an integrative multi-omics analysis of skin cutaneous melanoma using data from The Cancer Genome Atlas (TCGA) and validated our findings in independent cohorts. Multi-layered data, including transcriptomic, genomic, epigenetic, and immune landscape profiles, were analyzed using unsupervised clustering and machine learning approaches to define molecular subtypes. Functional assays and in silico drug screening were employed to explore subtype-specific vulnerabilities. Results Three robust molecular subtypes (CS1, CS2, CS3) were identified, each with distinct genomic alterations, tumor microenvironment characteristics, and clinical outcomes. The CS2 subtype was immunologically “hot,” characterized by high tumor mutational burden (TMB), elevated neoantigen load, strong immune infiltration, and activated IFN-γ signaling. CS2 tumors showed significant enrichment of immune checkpoint gene expression and were associated with favorable response to anti-PD-1 therapy in external validation cohorts. In contrast, CS1 and CS3 were immunologically “cold” with immune exclusion, high chromosomal instability, and activation of oncogenic pathways linked to immune evasion. Transcriptomic drug sensitivity modeling suggested that CS1 and CS3 may benefit from HSP90 or MEK inhibitors. Moreover, COL11A2 was identified as a subtype-enriched oncogenic driver predominantly expressed in CS1/CS3, and its silencing impaired tumor cell proliferation, invasion, and epithelial–mesenchymal transition (EMT) features. Conclusions This study presents a refined multi-omics classification of melanoma that reveals biologically and clinically distinct subtypes with divergent immune and therapeutic profiles. It offers a framework for subtype-specific treatment strategies, and identifies COL11A2 as a potential target in immune-cold melanomas.

METTL9 as a protein biomarker predicts the prognosis and immunotherapy response of skin-cutaneous melanoma

2025-06-12
Song Tang , Yiran Zhang , Simin Luo +4 more | Annals of Medicine and Surgery

Erratum: Bellocchio et al., “Sustained G<sub>q</sub>-Protein Signaling Disrupts Striatal Circuits via JNK”

2025-06-05
| Journal of Neuroscience

p90RSK modulates inter-and intracellular signaling in kidney diseases

2025-06-05
Ling Lin , Kebin Hu | Frontiers in Cell and Developmental Biology
The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also named as p90RSK. p90RSK is directly … The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also named as p90RSK. p90RSK is directly phosphorylated and activated by its immediate upstream mediator extracellular signal-regulated kinase (Erk1/2), followed by activating various signaling pathways through phosphorylating selective downstream substrates. Aberrant induction of p90RSK has been reported in various human diseases including kidney disease suggesting a pathogenic role of p90RSK in these diseases. In response to pathogenic cues, p90RSK not only mediates intracellular signal events leading to cell-specific phenotypes but also modulates intercellular communication impacting the adjacent cellular responses. In this review, we provide an update on the current knowledge regarding the roles of p90RSK-mediated intercellular and intracellular signaling in the pathogenesis and progression of kidney diseases.

Predicting overall survival benefit in previously untreated, unresectable or metastatic melanoma from improvement in progression-free survival: a correlation meta-analysis

2025-06-05
Peter G. Mohr , Murat Kurt , Swetha Srinivasan +5 more | Frontiers in Oncology
Objectives To evaluate the association between the treatment effects on progression-free survival (PFS) and overall survival (OS) for previously untreated, unresectable or metastatic melanoma. Methods A systematic literature review identified … Objectives To evaluate the association between the treatment effects on progression-free survival (PFS) and overall survival (OS) for previously untreated, unresectable or metastatic melanoma. Methods A systematic literature review identified eligible trials reporting PFS and OS. Bivariate random effects meta-analysis (BRMA) was performed to estimate the correlation between the hazard ratios (HRs) of OS (HR OS ) and PFS (HR PFS ), and sample size-weighted linear regression (WLR) was used to estimate a surrogacy equation which predict the HR OS from the HR PFS . Strength of the correlation obtained from BRMA and WLR models was assessed using published guidelines. Predictive performance of the WLR model was also evaluated internally by leave-one-out cross-validation (LOOCV) and externally against data from newly published trials. Further analyses included adjustments for BRAF mutation status, and restriction to phase III trials or trials evaluating immune checkpoint or BRAF/MEK inhibitors, without crossover or crossover-adjusted, or meeting proportional hazards assumption. Results BRMA and WLR estimated a correlation of 0.74 (95%CI: 0.51-0.87) and 0.81 (95%CI: 0.58-0.92), respectively. The estimated surrogacy equation derived from the WLR was lnHR OS = -0.05 + 0.50 × lnHR PFS with a statistically non-significant intercept (95% CI: -0.14 - 0.03) and a statistically significant slope (95% CI: 0.35 - 0.65). The surrogacy equation derived from the BRMA was lnHR OS = -0.11 + 0.36 × lnHR PFS with a statistically non-significant intercept (95% CI: -0.23 - 0.00) and a statistically significant slope (95% CI: 0.17 - 0.57). The predictive accuracy of the WLR was 95.8% in LOOCV. Across sensitivity analyses correlations between HR PFS and HR OS were ≥0.77 and ≥0.85 based on BRMA and WLR, respectively, and the accuracy of the WLR model in LOOCV was ≥88%. When predicting HR OS for newly published trials, the differences between the observed and model-predicted HR OS ’s were &amp;lt;0.05. Conclusions Results suggest a clinically meaningful and moderate trial-level correlation between PFS and OS across all analyses. The analyses and high accuracy of the surrogacy equations shown in internal and external validations can enable earlier prediction of treatment effects on OS from the improvements on PFS for previously untreated unresectable or metastatic melanoma.

Primary analysis of the EORTC-2139-MG/Columbus-AD trial: A randomized trial of adjuvant encorafenib and binimetinib versus placebo in high-risk stage II melanoma with a BRAF-V600E/K mutation.

2025-06-04
Alexander Christopher Jonathan Van Akkooi , Mario Mandalà , Michal Kiciński +7 more | Journal of Clinical Oncology
LBA9501 Background: Resected stage IIB/IIC melanoma has a high risk of recurrence. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies … LBA9501 Background: Resected stage IIB/IIC melanoma has a high risk of recurrence. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-PD-1 significantly improve recurrence-free survival (RFS) vs. placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF&amp;MEK inhibitor therapy showed benefit in high-risk stage III &amp; advanced disease, but its role in patients with fully resected BRAF -mutated stage IIB/IIC melanoma is unknown. Encorafenib and binimetinib could be considered a valuable alternative with a lower risk of chronic toxicities. Methods: Adult patients with fully resected stage IIB or IIC cutaneous melanoma who harbored a BRAF mutation V600E or K were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients. It was designed to demonstrate superiority regarding the primary endpoint RFS defined as time from randomization to the earliest of recurrence, new melanoma that was either ulcerated, thick or requiring a treatment other than surgery, or death with a power of 97% to detect a hazard ratio (HR) of 0.55 and 91% to detect a HR of 0.6 with a level of statistical significance of 0.025 for a one-sided log-rank test. Following a premature termination of accrual, the study was amended to become a randomized trial with safety as the primary and RFS a secondary endpoint. Results: Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 were equally randomized between enco+bini and placebo arms. Median age was 59 yrs and 54% were male. Data cutoff was on 19 Nov. 2024, after the last patient was discontinued from the study. Among randomized patients, 87 (79%) had BRAF V600E and 23 (21%) V600K mutation, 71 (65%) AJCC8 stage IIB and 39 (35%) IIC. Median follow-up was 12 and 7 months for enco+bini and placebo arms. Among 54 patients who initiated enco+bini, grade ≥3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. A serious treatment-related adverse event occurred in 1 patient. No patients died. In the enco+bini and placebo arm, respectively, 4 and 9 patients had an RFS event and 3 and 5 developed distant metastases. Descriptive RFS at 12 months was 86% (95% CI: 65-95%) in the enco+bini and 70% (95% CI: 46-85%) in the placebo arm, Distant Metastasis-Free Survival (DMFS) at 12 months was 92% (95% CI: 77-97%) for enco+bini and 82% (95% CI: 55-93%) for placebo arms. Conclusion: EORTC 2139 - Columbus-AD demonstrated a consistent safety profile for enco+bini. Descriptive analyses of efficacy show encouraging results of the combination of enco+bini for adjuvant treatment of stage IIB/C BRAF V600E/K cutaneous melanoma. Clinical trial information: NCT05270044 .

Encorafenib + Binimetinib Displays Promising Safety, Efficacy Signals in &lt;i&gt;BRAF&lt;/i&gt;&lt;sup&gt;V600E/K&lt;/sup&gt;&amp;#x2013;Mutated Melanoma

2025-06-03
| Default Digital Object Group

<scp>SOX10</scp>, <scp>MITF</scp>, and <scp>microRNAs</scp>: Decoding their interplay in regulating melanoma plasticity

2025-06-03
Xin Lai , Chunyan Luan , Z. Zhang +4 more | International Journal of Cancer
Abstract Recent studies show that the dysregulation of the transcription factor SOX10 is essential for the development and progression of melanoma. MicroRNAs (miRNAs) can regulate the expression of transcription factors … Abstract Recent studies show that the dysregulation of the transcription factor SOX10 is essential for the development and progression of melanoma. MicroRNAs (miRNAs) can regulate the expression of transcription factors at the post‐transcriptional level. The interactions between SOX10 and its targeting miRNAs form network motifs such as feedforward and feedback loops. Such motifs can result in nonlinear dynamics in gene expression levels, therefore playing a crucial role in regulating tumor proliferation and metastasis as well as the tumor's responses to therapies. Here, we reviewed and discussed the intricate interplay between SOX10 and miRNAs in melanoma biology including melanogenesis, phenotype switch, and therapy resistance. Additionally, we investigated the gene regulatory interactions in melanoma, identifying crucial network motifs that involve SOX10, MITF, and miRNAs. We also analyzed the expression levels of the components within these motifs. From a control theory perspective, we explained how these dynamics are linked to the phenotypic plasticity of melanoma cells. In summary, we underscored the importance of employing a data‐driven network biology approach to elucidate the complex regulatory mechanisms and identify driver network motifs within the melanoma network. This methodology facilitates a deeper understanding of the regulation of SOX10 and MITF by miRNAs in melanoma. The insight gained could potentially contribute to the development of miRNA‐based treatments, thereby enhancing the clinical management of this malignancy.

The safety and efficacy of dabrafenib plus trametinib for patients with brain metastatic melanoma: a systematic review and meta-analysis

2025-06-03
Mohammad Amin Habibi , Mohammad Sina Mirjani , Bardia Hajikarimloo +7 more | Discover Oncology
Brain metastases (BM) are common complications of metastatic cancer and typically occur in patients with melanoma. This study aims to investigate the dabrafenib plus trametinib for patients diagnosed with melanoma … Brain metastases (BM) are common complications of metastatic cancer and typically occur in patients with melanoma. This study aims to investigate the dabrafenib plus trametinib for patients diagnosed with melanoma brain metastasis (MBM). This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Embase, Scopus, and Web of Science were searched until January 1, 2025. Data on the neurological progression-free survival (PFS), overall survival (OS), radiological response rate, whether intracranial and total, and adverse events were collected. Quality assessment of the studies was conducted using the Newcastle-Ottawa Scale (NOS). The STATA version 17.0. has been used for analysis of the outcomes. Eleven studies met the inclusion criteria. Our results showed pooled 6-month OS rate of 76% (95% CI [69-84%]), 1-year OS of 45% (95% CI [38-51%]), 6-month PFS rate of 46% (95% CI [40-52%]), 1-year PFS of 22% (95% CI [13-30%]), disease control rate (DCR) of 71% (95% CI [61-80%]), overall response rate (ORR) of 45% (95% CI [33-57%]), complete response rate (CRR) of 4% (95% CI [0-11%]), partial response rate (PRR) of 47% (95% CI [31-63%]), progressive disease rate (PDR) of 29% (95% CI [13-44%]), and stable disease rate (SDR) of 21% (95% CI [14-27%]). The pooled intracranial CRR, intracranial PRR, intracranial SDR, and intracranial PDR were 4% [95% CI: 1-8%], 42% [95% CI: 32-53%], 24% [95% CI: 18-31%], and 24% [95% CI: 13-34%], respectively. These findings underscore the effectiveness of dabrafenib plus trametinib in managing MBM, offering potential benefits in disease control and patient outcomes.