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MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Tianzuo Zhan1,2, Giulia Ambrosi1, Anna Maxi Wandmacher1

  • 1Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, 69120, Heidelberg, Germany.

Nature Communications
|May 18, 2019
PubMed

Insights

MEK inhibitors activate Wnt/β-catenin signalling in colorectal cancer (CRC) by downregulating AXIN1. This unintended effect increases cancer stemness and relapse potential, highlighting a critical side effect of RAS pathway inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Aberrant Wnt signalling drives colorectal cancer (CRC) tumorigenesis and cancer stem cell maintenance.
  • The convergence of oncogenic pathways on Wnt signalling in CRC stem cell homeostasis is not well understood.

Purpose of the Study:

  • To investigate how other oncogenic pathways interact with Wnt signalling in CRC.
  • To identify therapeutic strategies targeting Wnt signalling in CRC.

Main Methods:

  • Large-scale compound screens in CRC cell lines.
  • CRISPR/Cas9 gene editing to generate APC mutations.
  • In vivo studies in murine intestine.
  • Analysis of patient-derived CRC organoids.

Main Results:

  • MEK1/2 inhibitors were identified as potent activators of Wnt/β-catenin signalling in CRC.
  • MEK inhibition led to downregulation of AXIN1, increasing Wnt activity.
  • MEK inhibitors synergized with APC mutations to enhance Wnt responses.
  • Increased Wnt activity, LGR5 levels, and stemness/relapse gene signatures were observed in CRC organoids.

Conclusions:

  • Clinically used MEK inhibitors inadvertently promote stem cell plasticity in CRC.
  • This reveals an unknown side effect of RAS pathway inhibition, impacting cancer stemness and relapse potential.

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