Melanoma and MAPK Pathways

Multi-omics and biophysical phosphoproteomics upon BRAF inhibition uncover functional networks of BRAFV600E-driven signaling

This study uses multi-omics and biophysical phosphoproteomics to analyze BRAFV600E signaling, identifying ETV3 as a new downstream regulator and revealing mechanisms of drug resistance.

Functional characterization of the 9q34.13 locus identifies RAPGEF1 as modulating risk for melanoma and nevi via RAS activation

This study identifies RAPGEF1 as a gene modulating melanoma and nevi risk through RAS activation, using fine-mapping, expression data, and functional assays.

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.

RAF isoform selectivity of MEK inhibitors and rational design of a covalent ARAF-MEK inhibitor

The paper investigates MEK inhibitor selectivity across RAF isoforms and develops a covalent ARAF-MEK inhibitor with improved potency.

In vitro reconstitutions suggest a general model for paradoxical activation of ARAF, BRAF, and CRAF by diverse RAF inhibitor types that does not rely on negative allostery.

This study shows that RAF inhibitors paradoxically activate ARAF, BRAF, and CRAF through dimerization, not negative allostery, by using biochemical assays and mass photometry.

Early overactivation of non-muscle myosin II during adaptation to combined BRAF and MEK inhibitors in dedifferentiating cutaneous melanomas

This study shows that non-muscle myosin II overactivation occurs in dedifferentiating melanomas adapting to BRAF and MEK inhibitors, and targeting NMII with BMi reduces drug-tolerant persister cell survival.

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.

GPCR-Gαq Signaling Drives Adaptive Resistance to MEK Inhibition in BRAF-Mutant Melanoma

This study identifies GPCR-Gαq signaling as a mechanism of adaptive resistance to MEK inhibition in BRAF-mutant melanoma, showing that targeting this pathway can restore drug sensitivity.

Cooperative and antagonistic interactions between sub-clones favour the co-existence of multiple resistance mechanisms in melanoma

This study shows that cooperative and antagonistic interactions between sub-clones in melanoma allow multiple resistance mechanisms to coexist, and identifies GSK-J4 as a potential therapeutic target.

Catestatin suppresses melanoma progression and drug resistance through multitargeted modulation of signaling pathways

This study shows that CST suppresses melanoma progression and drug resistance by modulating multiple signaling pathways.

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.

YAP1 drives aggressive and therapy resistant state in melanoma through reprogramming the chromatin and regulating immune evasive programs

This paper shows YAP1 promotes therapy resistance in melanoma by altering chromatin structure and immune evasion programs, and suggests TEAD inhibitors could overcome resistance and boost immune response.

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.

Characterization and inhibitor sensitivity of ARAF, BRAF, and CRAF complexes

This study compares the potency of thirteen RAF inhibitors against ARAF, BRAF, and CRAF isoforms, revealing differences in inhibitor selectivity and mechanism.

Concurrent inhibition of ICMT and RAF/MEK suppresses RAC1P29S-driven MAPKi resistance in BRAFV600E melanoma by regulating TAZ activity

This study shows that combining ICMT and MAPK inhibitors suppresses RAC1P29S-driven resistance in BRAFV600E melanoma by inhibiting TAZ activity.

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.

Palbociclib CDK4/6- and Crizotinib MET/ALK/ROS1-inhibitors Synergize to Enhance Senescence and Immune Recognition in Melanoma Cells Independently of BRAF/NRAS Status

This study shows that combining palbociclib and crizotinib enhances senescence and immune recognition in melanoma cells regardless of BRAF/NRAS status, reducing tumor growth.

Characterization of the BRAF interactome identifies BRAFV600ETP53 interaction in melanoma

The paper identifies a novel interaction between BRAFV600E and TP53 in melanoma, suggesting that BRAFV600E inactivates TP53, explaining the rarity of TP53 alterations in this cancer type.

Midkine Drives Reawakening of Dormant Melanoma Metastases

This paper identifies Midkine as a factor that disrupts melanoma dormancy by suppressing NR2F1 and altering signaling pathways, showing that targeting both Midkine and NR2F1 can limit metastasis and extend survival in mouse models.

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.

The epigenetic regulator TRIM24 controls melanoma cell dedifferentiation and resistance to treatment in melanoma

This study identifies TRIM24 as an epigenetic regulator that promotes melanoma cell dedifferentiation and treatment resistance, with potential as a druggable target.

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.

Characterization of MEK1/2 Degraders Uncovers a Kinase-Independent Role for MEK1/2 in the Stabilization and Maturation of CRAF

The paper identifies a kinase-independent role of MEK1/2 in stabilizing and maturing CRAF through direct binding, independent of catalytic activity.

Redirecting resistance evolution in BRAFV600 melanoma by inhibition of the peroxiredoxin-thioredoxin system

This study identifies KDM5B's role in regulating the PRDX/TXN ROS detoxification system in melanoma DTPs, showing that PRDX inhibition increases ROS vulnerability and delays resistance to MAPK inhibition.

Relationship between melanoma vemurafenib tolerance thresholds and metabolic pathway choice and Wnt signaling involvement

This study identifies that vemurafenib resistance in BRAFV600E melanomas is linked to metabolic pathway choices and Wnt/β-catenin signaling, with varying tolerance thresholds affecting mitochondrial and pentose phosphate pathway utilization.

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.