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.

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
  • 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • BRAF protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases

Associated data

  • GEO/GSE64550