Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Clonal Evolution
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Drug Resistance, Neoplasm / physiology*
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Female
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Humans
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Imidazoles / therapeutic use
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Indoles / therapeutic use
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Male
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Melanoma / drug therapy
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Melanoma / genetics*
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Melanoma / metabolism
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Middle Aged
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Mitogen-Activated Protein Kinases / metabolism*
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Oximes / therapeutic use
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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Sulfonamides / therapeutic use
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Vemurafenib
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ras Proteins / genetics
Substances
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Antineoplastic Agents
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Imidazoles
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Indoles
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Oximes
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Protein Kinase Inhibitors
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Sulfonamides
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Vemurafenib
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Phosphatidylinositol 3-Kinases
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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ras Proteins
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dabrafenib