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

Zheng Xue, Daniel J Vis, Alejandra Bruna, Tonci Sustic, Sake van Wageningen, Ankita Sati Batra, Oscar M Rueda, Evert Bosdriesz, Carlos Caldas, Lodewyk F A Wessels, René Bernards

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)719-729
Number of pages11
JournalCell Research
Issue number7
Publication statusPublished - Jul 2018


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


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