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Ref Type Journal Article
PMID (42562950)
Authors Fu Y, Amiot M, Kuzniak I, Jouenne F, Mourah S, Lebbé C, Dumaz N
Title RAF1 S257L/S259F hotspot mutations: functional characterization and intrinsic resistance to the RAS(ON) inhibitor daraxonrasib in melanoma.
Journal Vol Issue Date Pages Journal Short Title
Oncogene 2026 Aug 07 Oncogene
URL
Abstract Text Constitutive activation of the MAPK pathway is a hallmark of melanoma, leading to aberrant cell proliferation and survival. Although oncogenic mutations in NRAS and BRAF are well established, the functional and therapeutic significance of RAF1 mutations remains incompletely defined. Here, we identify RAF1 S257L and S259F as recurrent hotspot mutations in melanoma by integrating our hospital cohort with TCGA-SKCM. These conserved region 2 mutations relieve CRAF autoinhibition by reducing inhibitory Ser259 phosphorylation, resulting in elevated ERK signalling in a dimerization-dependent manner. Both mutants exhibit oncogenic activity and transform melanocytes in vitro, and the resulting transformed cells display intrinsic resistance to the RAS(ON) inhibitor daraxonrasib. Subsequent RAF-isoform knockdown and ectopic expression further demonstrate that daraxonrasib-resistant ERK activation is primarily driven by mutant CRAF. Importantly, in human melanoma cells, combined treatment with daraxonrasib and the MEK inhibitor cobimetinib effectively overcomes this mutant CRAF-driven resistance, producing greater suppression of p-ERK and cell proliferation than either agent alone and demonstrating marked synergy. Our findings establish RAF1 S257L/S259F as critical determinants of MAPK pathway activation and cellular response under daraxonrasib, provide mechanistic insights into intrinsic resistance to RAS(ON) inhibition, and underscore a therapeutic framework for genotype-guided combination strategies in RAF1-mutant melanoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS G12V melanoma sensitive Daraxonrasib Preclinical - Patient cell culture Actionable In a preclinical study, Rasonque (daraxonrasib) suppressed Erk activation and inhibited proliferation in transformed melanocytes expressing NRAS G12V in culture (PMID: 42562950). 42562950
NRAS G12V melanoma sensitive Cobimetinib Preclinical - Cell culture Actionable In a preclinical study, Cotellic (cobimetinib) suppressed Erk activation and inhibited proliferation in transformed melanocytes harboring NRAS G12V in culture (PMID: 42562950). 42562950