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

Zheng Xue1, Daniel J Vis1, Alejandra Bruna2

  • 1Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.

Cell Research
|May 26, 2018
PubMed

Insights

MEK inhibitors can be less effective due to feedback loops involving JNK-JUN signaling. Loss-of-function mutations in MAP3K1 or MAP2K4 disable this loop, making cancers sensitive to MEK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • The mitogen-activated protein kinase (MAPK) pathway is frequently activated in various cancers.
  • Drug development has primarily targeted RAF and MEK kinases within this pathway.

Purpose of the Study:

  • To investigate the feedback mechanisms that regulate MEK inhibitor efficacy.
  • To identify biomarkers predicting response to MEK inhibitors.
  • To explore novel therapeutic targets in combination with MEK inhibitors.

Main Methods:

  • Analysis of JNK-JUN signaling activation upon MEK inhibition.
  • Investigation of DUSP4 and HER Receptor Tyrosine Kinases' roles in feedback.
  • Assessment of MAP3K1 and MAP2K4 mutation status in Patient Derived Xenograft (PDX) tumors.
  • Correlation of mutation status with response to MEK inhibitors.

Main Results:

  • MEK inhibition activates JNK-JUN signaling by suppressing DUSP4, leading to HER activation and MAPK pathway stimulation, thus counteracting MEK inhibition.
  • Loss-of-function mutations in MAP3K1 or MAP2K4 prevent JNK-JUN activation, rendering cancers sensitive to MEK inhibitors.
  • MAP3K1 and MAP2K4 mutation status is a significant predictor of MEK inhibitor response in PDX tumors.

Conclusions:

  • MAP3K1 and MAP2K4 mutations create sensitivity to MEK inhibitors by disrupting a key feedback loop.
  • Cancers with MAP3K1 or MAP2K4 mutations, common in breast, prostate, and colon cancers, may benefit from MEK inhibitors.
  • MAP3K1 and MAP2K4 represent potential therapeutic targets for combination therapy with MEK inhibitors.

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