The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies Journal Article
| Authors: | 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.; Collisson, E. A.; Algazi, A.; Robinson, E.; Osman, I.; Muñoz-Couselo, E.; Cortes, J.; Frederick, D. T.; Cooper, Z. A.; McMahon, M.; Marchetti, A.; Rosell, R.; Flaherty, K. T.; Wargo, J. A.; Bivona, T. G. |
| Article 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. © 2015 Nature America, Inc. All rights reserved. |
| Keywords: | mitogen activated protein kinase; treatment response; raf protein; drug efficacy; nonhuman; antineoplastic agent; cell viability; apoptosis; cancer resistance; nucleotide sequence; cancer cell; melanoma cell; cell fractionation; transcription factor yap1; short hairpin rna; non small cell lung cancer; molecularly targeted therapy; vemurafenib; trametinib; human; priority journal; article |
| Journal Title: | Nature Genetics |
| Volume: | 47 |
| Issue: | 3 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-03-01 |
| Start Page: | 250 |
| End Page: | 256 |
| Language: | English |
| DOI: | 10.1038/ng.3218 |
| PROVIDER: | scopus |
| PUBMED: | 25665005 |
| PMCID: | PMC4930244 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
