MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

Cell Res. 2018 Jul;28(7):719-729. doi: 10.1038/s41422-018-0044-4. Epub 2018 May 24.


Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Heterografts
  • Humans
  • Loss of Function Mutation
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Kinase 4 / genetics*
  • MAP Kinase Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 1 / genetics*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*


  • AZD 6244
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Mitogen-Activated Protein Kinase Kinases