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. Collisson; Alain 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

doi:10.1038/ng.3218

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 journal › Article › peer-review

271 Scopus citations

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 language	English (US)
Pages (from-to)	250-256
Number of pages	7
Journal	Nature Genetics
Volume	47
Issue number	3
DOIs	https://doi.org/10.1038/ng.3218
State	Published - Feb 25 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics
General Medicine

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Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J. J., Lu, X., Pham, L., Wang, M. M., Karachaliou, N., Cao, M. G., Manzano, J. L., Ramirez, J. L., Torres, J. M. S., Buttitta, F., Rudin, C. M., ... 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

Lin, L, Sabnis, AJ, Chan, E, Olivas, V, Cade, L, Pazarentzos, E, Asthana, S, Neel, D, Yan, JJ, Lu, X, Pham, L, Wang, MM, Karachaliou, N, Cao, MG, Manzano, JL, Ramirez, JL, Torres, JMS, Buttitta, F, Rudin, CM, Collisson, EA, Algazi, A, Robinson, E, Osman, I, Muñoz-Couselo, E, Cortes, J, Frederick, DT, Cooper, ZA, Mcmahon, M, Marchetti, A, Rosell, R, Flaherty, KT, Wargo, JA & Bivona, TG 2015, 'The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies', Nature Genetics, vol. 47, no. 3, pp. 250-256. https://doi.org/10.1038/ng.3218

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title = "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.",

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

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AU - Sabnis, Amit J.

AU - Chan, Elton

AU - Olivas, Victor

AU - Cade, Lindsay

AU - Pazarentzos, Evangelos

AU - Asthana, Saurabh

AU - Neel, Dana

AU - Yan, Jenny Jiacheng

AU - Lu, Xinyuan

AU - Pham, Luu

AU - Wang, Mingxue M.

AU - Karachaliou, Niki

AU - Cao, Maria Gonzalez

AU - Manzano, Jose Luis

AU - Ramirez, Jose Luis

AU - Torres, Jose Miguel Sanchez

AU - Buttitta, Fiamma

AU - Rudin, Charles M.

AU - Collisson, Eric A.

AU - Algazi, Alain

AU - Robinson, Eric

AU - Osman, Iman

AU - Muñoz-Couselo, Eva

AU - Cortes, Javier

AU - Frederick, Dennie T.

AU - Cooper, Zachary A.

AU - Mcmahon, Martin

AU - Marchetti, Antonio

AU - Rosell, Rafael

AU - Flaherty, Keith T.

AU - Wargo, Jennifer A.

AU - Bivona, Trever G.

PY - 2015/2/25

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N2 - 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.

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

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