The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies Academic Article uri icon

Overview

MeSH Major

  • Adaptor Proteins, Signal Transducing
  • MAP Kinase Kinase Kinases
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf

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

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4930244

Digital Object Identifier (DOI)

  • 10.1038/ng.3218

PubMed ID

  • 25665005

Additional Document Info

start page

  • 250

end page

  • 6

volume

  • 47

number

  • 3