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

Moriceau G, Hugo W, Hong A, Shi H, Kong X, Yu CC, Koya RC, Samatar AA, Khanlou N, Braun J, Ruchalski K, Seifert H, Larkin J, Dahlman KB, Johnson DB, Algazi A, Sosman JA, Ribas A, Lo RS
Cancer Cell. 2015 27 (2): 240-56

PMID: 25600339 · PMCID: PMC4326539 · DOI:10.1016/j.ccell.2014.11.018

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (9)

Cell Line, Tumor Drug Resistance, Neoplasm Humans MAP Kinase Signaling System Melanoma Molecular Targeted Therapy Mutation Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf

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