| Literature DB >> 25600339 |
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.
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.Entities:
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Year: 2015 PMID： 25600339 PMCID： PMC4326539 DOI： 10.1016/j.ccell.2014.11.018
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743