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PMID (36901951)
Authors Krebs FS, Moura B, Missiaglia E, Aedo-Lopez V, Michielin O, Tsantoulis P, Bisig B, Trimech M, Zoete V, Homicsko K
Title Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma.
Journal Vol Issue Date Pages Journal Short Title
International journal of molecular sciences 24 5 2023 Feb 24 Int J Mol Sci
URL
Abstract Text The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.

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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
MAP2K1 C121S MAP2K1 P124R melanoma predicted - sensitive Trametinib Case Reports/Case Series Actionable In a clinical case study, Mekinist (trametinib) resulted in a partial response after two months of treatment in a patient with melanoma harboring MAP2K1 C121S and MAP2K1 P124R (PMID: 36901951). 36901951