Melanoma and MAPK Pathways

Spatial modulation of RAF by RAF/MEK glue enables full-dose combination with pan-RAF inhibitor and potent RAS-mutant tumor-selective MAPK and growth inhibition

The paper shows RAF/MEK glues enable full-dose combination with pan-RAF inhibitors, enhancing tumor-selective MAPK inhibition and tumor regression in RAS-mutant models.

Inhibition of BRN2 in Melanoma Reverses Anoikis Resistance and Sensitizes Cells to Killing by Vemurafenib

This paper shows that inhibiting BRN2 in melanoma cells reverses anoikis resistance and increases sensitivity to Vemurafenib.

Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the RAPGEF3/4 signaling dependency in primary melanoma

This study identifies TXNIP as a downstream effector of EPAC signaling in primary melanoma, showing its role in redox regulation and melanoma progression through mTORC1 and HIF-1 pathways.

Mechanism of MEK1 phosphorylation by the N-terminal acidic motif mediated asymmetric BRAF dimer

The paper presents the first X-ray structure of an NtA-mediated asymmetric BRAF dimer bound to MEK1, showing it is a catalytically active state, not an intermediate in BRAF activation.

Selective mRNA translation determines adaptative mutability of melanoma cells to anti-BRAF/MEK combination therapy

This study shows that translational control of 53BP1 mRNA regulates adaptive mutability in melanoma cells, and targeting eIF4A reduces resistance to BRAF/MEK inhibitors.

Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma

This study identifies RAS(ON) inhibitors effective against NRAS-mutated melanoma and reveals resistance mechanisms through Ppia and Map2k1 mutations.

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

This study identifies MAFG as a driver of melanoma progression by interacting with MITF to alter gene expression and promote a dedifferentiated melanoma phenotype.

Uncovering the mechanistic basis of intracellular Raf inhibitor sensitivity reveals synergistic cotreatment strategies

This study identifies how Raf inhibitor potency varies with Raf activity and shows that cobimetinib enhances sensitivity to DFG-out inhibitors by disrupting autoinhibited Raf-Mek complexes.

Translational control of AMPK activity in melanoma

This study shows eIF4F inhibition increases AMPK activity in BRAF-mutant melanoma cells by both reducing LKB1 and enhancing PP2A activity, suggesting new therapeutic strategies.

RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway

This study identifies RIPOR2 as a downstream target of the RAS/ERK pathway that promotes multinucleation in melanoma cells, contributing to aneuploidy and tumor progression.

MAPK Pathway Inhibition Reshapes Kinase Chemical Probe Reactivity Reflecting Cellular Activation States

This study uses ABPP to show how MAPK pathway inhibitors alter kinase residue reactivity, reflecting conformational changes and resistance mechanisms in melanoma cells.

SOX2 empowers a rapid tumorigenic programme from the tumour resistant population in the skin

This study identifies SOX2 as a key driver of rapid tumorigenesis from a previously resistant skin cell population in mice, with implications for human cutaneous squamous cell carcinoma.

FRA1 drives melanoma metastasis through an actionable transcriptional network

This study identifies FRA1 as a driver of melanoma metastasis and shows that targeting its downstream genes AXL, CDK6, and FSCN1 suppresses metastasis and improves survival.

Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma.

The paper identifies distinct gene expression programs driven by MITF, TFEB, and TFE3 in melanoma, revealing their functional specialization in regulating differentiation, metabolism, and immune infiltration.

A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition

This study identifies FAK signaling as a critical target for overcoming Rac1-driven MAPK resistance in melanoma and shows that combining RAF/MEK and FAK inhibitors is effective.

MAPK and mTORC1 signaling converge on Cyclin D to enable cell-cycle re-entry in melanoma persister cells

The paper identifies Cyclin D1 accumulation as a critical bottleneck for cell-cycle re-entry in drug-treated melanoma cells, driven by MAPK and mTORC1 signaling integration.

Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma

This study shows that a ubiquitin-resistant ICER mutant suppresses melanoma progression and prolongs survival in a zebrafish model of BRAFV600E-driven melanoma.

Cx43 Enhances Response to BRAF/MEK Inhibitors by Reducing DNA Repair Capacity

This study shows that Cx43 enhances the effectiveness of BRAF/MEKi by reducing DNA repair, leading to increased DNA damage and cellular senescence, and proposes a novel therapeutic approach using sEVs.

Resistance to BRAF inhibitors drives melanoma sensitivity to Chk1 inhibition

This study shows BRAF inhibitor-resistant melanoma cells are more sensitive to Chk1 inhibition due to increased replication stress, suggesting Chk1i could overcome MAPK inhibitor resistance.

Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition

The paper investigates early signaling and transcriptional changes in melanoma cells under BRAF inhibitor treatment, identifying SFK activation as a compensatory mechanism and demonstrating its sensitivity to co-inhibition.

Antagonistic Roles for MITF and TFE3 in Melanoma Plasticity

This study identifies TFE3 and the non-canonical mTORC1 pathway as regulators of melanoma cell state plasticity, showing MITF suppresses the mesenchymal phenotype by modulating TFE3 expression.

Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: Implications for the involvement of pirin

This study shows that CCG-257081 overcomes melanoma resistance by inducing apoptosis and inhibiting the Rho/MRTF pathway, with pirin playing a role in this process.

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment

This study shows that dual FGFR/VEGFR inhibition causes regression of acral melanoma by targeting the tumor microenvironment rather than directly killing cancer cells.

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

This study shows ERK hyperactivation in keratinocytes causes impaired adhesion and drives Grover disease, supporting MEK inhibition as a potential therapy.

Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma

This study uses computational modeling and preclinical data to identify optimal dosing strategies for panRAF and MEK inhibitors in melanoma, revealing distinct dose requirements based on NRAS vs BRAF mutations.

Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance

The paper models MAPK signaling in BRAFV600E melanoma cells to show how allostery and rewiring lead to drug resistance.

DNA replication during acute MEK inhibition drives acquisition of resistance through amplification of the BRAF oncogene

The paper shows that DNA replication during MEK inhibition drives BRAF amplification and resistance in COLO205 cells, and that blocking cell cycle entry can suppress resistance.

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells

The paper shows that the AP-1 transcription factor network explains cellular plasticity in melanoma by regulating differentiation states and responses to MAPK inhibitors.

Sustained experimental activation of FGF8/ERK in the developing chicken spinal cord reproducibly models early events in ERK-mediated tumorigenesis

The paper shows sustained ERK1/2 activation in chicken embryos induces neoplasia in the spinal cord, mimicking early ERK-mediated tumorigenesis.