Journal
CANCER DISCOVERY
Volume 4, Issue 1, Pages 80-93Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0642
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Funding
- Stand Up To Cancer Innovative Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-IRG0409]
- National Cancer Institute [K22CA151638, 1R01CA176111, 1P01CA168585]
- Burroughs Wellcome Fund
- American Skin Association
- Melanoma Research Alliance
- Sidney Kimmel Foundation for Cancer Research
- Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research
- Ian Copeland Melanoma Fund
- Harry J. Lloyd Charitable Trust
- National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute [UL1TR000124]
- Seaver Institute
- Wesley Coyle Memorial Fund
- Louis Belley and Richard Schnarr Fund
- Dr. Robert Vigen Memorial Fund
- Garcia-Corsini Family Fund
- Ruby Family Foundation
- Association of American Cancer Institutes
- National Health and Medical Research Council of Australia
- Cancer Institute New South Wales
- American Cancer Society
- NCI [5K24 CA097588]
- NATIONAL CANCER INSTITUTE [K12CA090625, K22CA151638, K24CA097588, R01CA176111, P01CA168585, P30CA016042] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000124] Funding Source: NIH RePORTER
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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. SIGNIFICANCE: This study provides critical insights into how human BRAF-mutant melanoma, a malignancy with marked mutational burden, escapes from BRAF inhibitors. Understanding the core resistance pathways as well as tumor heterogeneity, fitness, and mutational patterns, which emerge under drug selection, lays a foundation to rationalize clinical studies and investigate mechanisms of disease progression. (C)2013 AACR.
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