In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. LB-239-LB-239
Abstract:
Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially but only transiently effective in some but not all BRAF mutant patients, and largely ineffective in RAS mutant patients because of resistance. Through a genetic screen in BRAF mutant tumor cells, we show that the Hippo pathway effector YAP acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy. Combined YAP and RAF-MEK inhibition was synthetically lethal not only in several BRAF mutant tumor types but also in RAS mutant tumors. Increased YAP in BRAFV600E patient tumors was a biomarker of worse initial response to RAF inhibition in patients, establishing the clinical relevance of our findings. Our data uncover YAP as a novel mechanism of resistance to RAF-MEK targeted therapy. The findings unveil the synthetic lethality of YAP and RAF-MEK co-suppression as a promising strategy to enhance response and patient survival. Citation Format: Luping Lin, Amit Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue Wang, Niki Karachaliou, Maria G. Cao, Jose L. Manzano, Jose L. Ramirez, Jose M. Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Munoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona. The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-239. doi:10.1158/1538-7445.AM2015-LB-239
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-LB-239
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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