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Cancer Cell. 2015 Feb 9;27(2):240-56. doi: 10.1016/j.ccell.2014.11.018. Epub 2015 Jan 15.

Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.

Author information

1
Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Division of Oncology, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
4
Discovery Oncology, Merck Research Laboratories, Boston, MA 02115, USA.
5
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7
Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
8
Department of Medicine, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
9
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
10
Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
11
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
12
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
13
Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rlo@mednet.ucla.edu.

Abstract

Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.

PMID:
25600339
PMCID:
PMC4326539
DOI:
10.1016/j.ccell.2014.11.018
[Indexed for MEDLINE]
Free PMC Article

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