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.
authors: 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.
authors: Luping
authors: L
authors: Lin
authors: 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.
authors: Amit J
authors: AJ
authors: Sabnis
authors: 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.
authors: Elton
authors: E
authors: Chan
authors: 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.
authors: Victor
authors: V
authors: Olivas
authors: 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.
authors: Lindsay
authors: L
authors: Cade
authors: 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.
authors: Evangelos
authors: 0000000254531646
authors: E
authors: Pazarentzos
authors: 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.
authors: Saurabh
authors: S
authors: Asthana
authors: 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.
authors: Dana
authors: D
authors: Neel
authors: 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.
authors: Jenny Jiacheng
authors: JJ
authors: Yan
authors: 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.
authors: Xinyuan
authors: X
authors: Lu
authors: 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.
authors: Luu
authors: L
authors: Pham
authors: 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.
authors: Mingxue M
authors: MM
authors: Wang
authors: Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors: Niki
authors: N
authors: Karachaliou
authors: Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors: Maria Gonzalez
authors: MG
authors: Cao
authors: Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors: Jose Luis
authors: JL
authors: Manzano
authors: Translational Oncology Laboratory, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Fundació Institut Recerca Germans Trias i Pujol (IGTP), Barcelona, Spain.
authors: Jose Luis
authors: JL
authors: Ramirez
authors: Medical Oncology Service, Hospital Universitario de La Princesa, Madrid, Spain.
authors: Jose Miguel Sanchez
authors: JM
authors: Torres
authors: Center for Predictive Molecular Medicine, University Foundation, Chieti-Pescara, Chieti, Italy.
authors: Fiamma
authors: F
authors: Buttitta
authors: 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.
authors: Charles M
authors: CM
authors: Rudin
authors: 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.
authors: Eric A
authors: EA
authors: Collisson
authors: 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.
authors: Alain
authors: A
authors: Algazi
authors: Ronald O. Perelman Department of Dermatology, Medicine and Urology, New York University Cancer Institute, New York, New York, USA.
authors: Eric
authors: E
authors: Robinson
authors: Ronald O. Perelman Department of Dermatology, Medicine and Urology, New York University Cancer Institute, New York, New York, USA.
authors: Iman
authors: I
authors: Osman
authors: Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Eva
authors: E
authors: Muñoz-Couselo
authors: Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Javier
authors: J
authors: Cortes
authors: 1] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Massachusetts General Hospital Comprehensive Cancer Center, Boston, Massachusetts, USA.
authors: Dennie T
authors: DT
authors: Frederick
authors: 1] Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Zachary A
authors: ZA
authors: Cooper
authors: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors: Martin
authors: M
authors: McMahon
authors: Center for Predictive Molecular Medicine, University Foundation, Chieti-Pescara, Chieti, Italy.
authors: Antonio
authors: A
authors: Marchetti
authors: Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors: Rafael
authors: R
authors: Rosell
authors: 1] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Massachusetts General Hospital Comprehensive Cancer Center, Boston, Massachusetts, USA.
authors: Keith T
authors: KT
authors: Flaherty
authors: 1] Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Jennifer A
authors: JA
authors: Wargo
authors: 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.
authors: Trever G
authors: TG
authors: Bivona
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D057809:HEK293 Cells; D019073:HT29 Cells; D064593:Heterografts; D000090683:Hippo Signaling Pathway; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases