The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies

Luping Lin, Amit J. Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue M. Wang, Niki Karachaliou, Maria Gonzalez Cao, Jose Luis Manzano, Jose Luis Ramirez, Jose Miguel Sanchez Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. CollissonAlain Algazi, Eric Robinson, Iman Osman, Eva Muñoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin Mcmahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)250-256
Number of pages7
JournalNature Genetics
Volume47
Issue number3
DOIs
Publication statusPublished - Feb 25 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., ... Bivona, T. G. (2015). The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nature Genetics, 47(3), 250-256. https://doi.org/10.1038/ng.3218