Journal Article

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

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

2015

Overview

Trever Bivona and colleagues show that the Hippo pathway effector YAP promotes resistance to RAF and MEK inhibitor therapy in multiple types of BRAF -mutant tumors. The findings suggest that combined suppression of YAP and RAF-MEK signaling might enhance treatment response and prevent drug resistance. Resistance to RAF- and MEK-targeted therapy is a major clinical challenge 1 , 2 , 3 , 4 . 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 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/89 / 13/95 / 38/91 / 692/699/67/1059/602 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Agriculture / Animal Genetics and Genomics / Animals / Antimitotic agents / Antineoplastic agents / Biomarkers, Tumor - genetics / Biomedicine / Cancer Research / Cancer therapies / Cell Line, Tumor / Charitable foundations / Colorectal cancer / Design of experiments / Drug resistance / Drug Resistance, Neoplasm - genetics / Female / Gene Function / Gene Knockdown Techniques / Gene mutations / Genes, ras / Genetic aspects / Health aspects / HEK293 Cells / Heterografts / HT29 Cells / Human Genetics / Humans / Kinases / letter / Lung cancer / MAP Kinase Kinase Kinases - antagonists & inhibitors / MAP Kinase Kinase Kinases - genetics / MAP Kinase Kinase Kinases - metabolism / MAP Kinase Signaling System - drug effects / MAP Kinase Signaling System - genetics / Melanoma / Mice / Mice, Inbred NOD / Mice, SCID / Molecular Targeted Therapy / Mutation / Phosphoproteins - genetics / Phosphoproteins - metabolism / Protein Kinase Inhibitors - pharmacology / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Thyroid cancer / Transcription Factors / Tumors