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

Gatien Moriceau; Willy Hugo; Aayoung Hong; Hubing Shi; Xiangju Kong; Clarissa C Yu; Richard C Koya; Ahmed A Samatar; Negar Khanlou; Jonathan Braun; Kathleen Ruchalski; Heike Seifert; James Larkin; Kimberly B Dahlman; Douglas B Johnson; Alain Algazi; Jeffrey A Sosman; Antoni Ribas; Roger S Lo

doi:10.1016/j.ccell.2014.11.018

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

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

Authors

Gatien Moriceau¹, Willy Hugo¹, Aayoung Hong², Hubing Shi¹, Xiangju Kong¹, Clarissa C Yu¹, Richard C Koya³, Ahmed A Samatar⁴, Negar Khanlou⁵, Jonathan Braun⁶, Kathleen Ruchalski⁷, Heike Seifert⁸, James Larkin⁸, Kimberly B Dahlman⁹, Douglas B Johnson¹⁰, Alain Algazi¹¹, Jeffrey A Sosman¹⁰, Antoni Ribas¹², Roger S Lo¹³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Drug Resistance, Neoplasm / genetics*
Humans
MAP Kinase Signaling System / genetics
Melanoma / drug therapy*
Melanoma / genetics*
Melanoma / pathology
Molecular Targeted Therapy
Mutation
Protein Kinase Inhibitors / administration & dosage
Proto-Oncogene Proteins B-raf / genetics*

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

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