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

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

doi:10.1038/ng.3218

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

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

Authors

Luping Lin¹, Amit J Sabnis², Elton Chan¹, Victor Olivas¹, Lindsay Cade¹, Evangelos Pazarentzos¹, Saurabh Asthana¹, Dana Neel¹, Jenny Jiacheng Yan¹, Xinyuan Lu¹, Luu Pham¹, Mingxue M Wang¹, Niki Karachaliou³, Maria Gonzalez Cao³, Jose Luis Manzano⁴, Jose Luis Ramirez⁵, Jose Miguel Sanchez Torres⁶, Fiamma Buttitta⁷, Charles M Rudin⁸, Eric A Collisson¹, Alain Algazi¹, Eric Robinson⁹, Iman Osman⁹, Eva Muñoz-Couselo¹⁰, Javier Cortes¹⁰, Dennie T Frederick¹¹, Zachary A Cooper¹², Martin McMahon¹³, Antonio Marchetti⁷, Rafael Rosell³, Keith T Flaherty¹¹, Jennifer A Wargo¹², Trever G Bivona¹

Affiliations

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.

PMID: 25665005
PMCID: PMC4930244
DOI: 10.1038/ng.3218

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Biomarkers, Tumor / genetics
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Female
Gene Knockdown Techniques
Genes, ras
HEK293 Cells
HT29 Cells
Heterografts
Hippo Signaling Pathway
Humans
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
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
Transcription Factors
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Biomarkers, Tumor
Phosphoproteins
Protein Kinase Inhibitors
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
BRAF protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins B-raf
MAP Kinase Kinase Kinases

Associated data

GEO/GSE64550

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding