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


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.

SUBMITTER: Lin L 

PROVIDER: S-EPMC4930244 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Lin Luping L   Sabnis Amit J AJ   Chan Elton E   Olivas Victor V   Cade Lindsay L   Pazarentzos Evangelos E   Asthana Saurabh S   Neel Dana D   Yan Jenny Jiacheng JJ   Lu Xinyuan X   Pham Luu L   Wang Mingxue M MM   Karachaliou Niki N   Cao Maria Gonzalez MG   Manzano Jose Luis JL   Ramirez Jose Luis JL   Torres Jose Miguel Sanchez JM   Buttitta Fiamma F   Rudin Charles M CM   Collisson Eric A EA   Algazi Alain A   Robinson Eric E   Osman Iman I   Muñoz-Couselo Eva E   Cortes Javier J   Frederick Dennie T DT   Cooper Zachary A ZA   McMahon Martin M   Marchetti Antonio A   Rosell Rafael R   Flaherty Keith T KT   Wargo Jennifer A JA   Bivona Trever G TG  

Nature genetics 20150209 3


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  ...[more]

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