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Cancer Discov. 2014 Jan;4(1):80-93. doi: 10.1158/2159-8290.CD-13-0642. Epub 2013 Nov 21.

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

Shi H#1,2, Hugo W#1,2, Kong X1,2, Hong A1,3,2, Koya RC4,2, Moriceau G1,2, Chodon T5,2, Guo R5,2, Johnson DB6,7, Dahlman KB8,7, Kelley MC9,7, Kefford RF10, Chmielowski B5,11,2, Glaspy JA5,11,2, Sosman JA6,7, van Baren N12, Long GV10, Ribas A1,5,11,3,2, Lo RS1,11,3,2.

Author information

1
Division of Dermatology, Department of Medicine.
2
David Geffen School of Medicine, University of California, LA, California 90095-1662 USA.
3
Department of Molecular and Medical Pharmacology.
4
Division of Surgical Oncology, Department of Surgery.
5
Division of Hematology & Oncology, Department of Medicine.
6
Department of Medicine.
7
Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
8
Department of Cancer Biology.
9
Department of Surgery.
10
Melanoma Institute of Australia, Westmead Millenium Institute, Westmead Hospital, University of Sydney, New South Wales, Australia.
11
Jonsson Comprehensive Cancer Center.
12
Ludwig Institute for Cancer Research, Brussels Branch, Belgium.
#
Contributed equally

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.

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PMID:
24265155
PMCID:
PMC3936420
DOI:
10.1158/2159-8290.CD-13-0642
[Indexed for MEDLINE]
Free PMC Article

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