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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

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. V600EBRAF, expressed at supraphysiological levels because of V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed V600EBRAF via a regulatory interface at R662 of V600EBRAF. 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.

Original languageEnglish (US)
Pages (from-to)240-256
Number of pages17
JournalCancer Cell
Volume27
Issue number2
DOIs
StatePublished - Feb 9 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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