Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.

Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB, Kelley MC, Kefford RF, Chmielowski B, Glaspy JA, Sosman JA, van Baren N, Long GV, Ribas A, Lo RS
Cancer Discov. 2014 4 (1): 80-93

PMID: 24265155 · PMCID: PMC3936420 · DOI:10.1158/2159-8290.CD-13-0642

BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.

MeSH Terms (25)

Adult Aged Aged, 80 and over Antineoplastic Agents Cell Line, Tumor Clonal Evolution Drug Resistance, Neoplasm Female Humans Imidazoles Indoles Male Melanoma Middle Aged Mitogen-Activated Protein Kinases Oximes Phosphatidylinositol 3-Kinases Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase ras Proteins Skin Neoplasms Sulfonamides Vemurafenib

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