1. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies
- Author
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Lin, Luping, Sabnis, Amit J, Chan, Elton, Olivas, Victor, Cade, Lindsay, Pazarentzos, Evangelos, Asthana, Saurabh, Neel, Dana, Yan, Jenny Jiacheng, Lu, Xinyuan, Pham, Luu, Wang, Mingxue M, Karachaliou, Niki, Cao, Maria Gonzalez, Manzano, Jose Luis, Ramirez, Jose Luis, Torres, Jose Miguel Sanchez, Buttitta, Fiamma, Rudin, Charles M, Collisson, Eric A, Algazi, Alain, Robinson, Eric, Osman, Iman, Muñoz-Couselo, Eva, Cortes, Javier, Frederick, Dennie T, Cooper, Zachary A, McMahon, Martin, Marchetti, Antonio, Rosell, Rafael, Flaherty, Keith T, Wargo, Jennifer A, and Bivona, Trever G
- Subjects
Agricultural ,Veterinary and Food Sciences ,Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Agricultural Biotechnology ,Cancer ,Adaptor Proteins ,Signal Transducing ,Animals ,Biomarkers ,Tumor ,Cell Line ,Tumor ,Drug Resistance ,Neoplasm ,Female ,Gene Knockdown Techniques ,Genes ,ras ,HEK293 Cells ,HT29 Cells ,Heterografts ,Hippo Signaling Pathway ,Humans ,MAP Kinase Kinase Kinases ,MAP Kinase Signaling System ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Molecular Targeted Therapy ,Mutation ,Phosphoproteins ,Protein Kinase Inhibitors ,Protein Serine-Threonine Kinases ,Proto-Oncogene Proteins B-raf ,Transcription Factors ,YAP-Signaling Proteins ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - 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.
- Published
- 2015