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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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