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Nat Genet. 2015 Mar;47(3):250-6. doi: 10.1038/ng.3218. Epub 2015 Feb 9.

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

Author information

1
1] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
2
1] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of California, San Francisco, San Francisco, California, USA.
3
Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
4
Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
5
Translational Oncology Laboratory, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Fundació Institut Recerca Germans Trias i Pujol (IGTP), Barcelona, Spain.
6
Medical Oncology Service, Hospital Universitario de La Princesa, Madrid, Spain.
7
Center for Predictive Molecular Medicine, University Foundation, Chieti-Pescara, Chieti, Italy.
8
1] Molecular Chemistry and Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9
Ronald O. Perelman Department of Dermatology, Medicine and Urology, New York University Cancer Institute, New York, New York, USA.
10
Vall d'Hebron Institute of Oncology, Barcelona, Spain.
11
1] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Massachusetts General Hospital Comprehensive Cancer Center, Boston, Massachusetts, USA.
12
1] Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
13
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

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.

PMID:
25665005
PMCID:
PMC4930244
DOI:
10.1038/ng.3218
[Indexed for MEDLINE]
Free PMC Article

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