| Literature DB >> 25665005 |
Luping Lin1, Amit J Sabnis2, Elton Chan1, Victor Olivas1, Lindsay Cade1, Evangelos Pazarentzos1, Saurabh Asthana1, Dana Neel1, Jenny Jiacheng Yan1, Xinyuan Lu1, Luu Pham1, Mingxue M Wang1, Niki Karachaliou3, Maria Gonzalez Cao3, Jose Luis Manzano4, Jose Luis Ramirez5, Jose Miguel Sanchez Torres6, Fiamma Buttitta7, Charles M Rudin8, Eric A Collisson1, Alain Algazi1, Eric Robinson9, Iman Osman9, Eva Muñoz-Couselo10, Javier Cortes10, Dennie T Frederick11, Zachary A Cooper12, Martin McMahon13, Antonio Marchetti7, Rafael Rosell3, Keith T Flaherty11, Jennifer A Wargo12, Trever G Bivona1.
Abstract
Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.Entities:
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Year: 2015 PMID： 25665005 PMCID： PMC4930244 DOI： 10.1038/ng.3218
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330