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

Tianzuo Zhan, Giulia Ambrosi, Anna Maxi Wandmacher, Benedikt Rauscher, Johannes Betge, Niklas Rindtorff, Ragna S. Häussler, Isabel Hinsenkamp, Leonhard Bamberg, Bernd Hessling, Karin Müller-Decker, Gerrit Erdmann, Elke Burgermeister, Matthias P. Ebert and Michael Boutros ()
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Tianzuo Zhan: German Cancer Research Center (DKFZ) and Heidelberg University
Giulia Ambrosi: German Cancer Research Center (DKFZ) and Heidelberg University
Anna Maxi Wandmacher: German Cancer Research Center (DKFZ) and Heidelberg University
Benedikt Rauscher: German Cancer Research Center (DKFZ) and Heidelberg University
Johannes Betge: German Cancer Research Center (DKFZ) and Heidelberg University
Niklas Rindtorff: German Cancer Research Center (DKFZ) and Heidelberg University
Ragna S. Häussler: NMI Natural and Medical Sciences Institute at the University of Tübingen
Isabel Hinsenkamp: Heidelberg University
Leonhard Bamberg: Heidelberg University
Bernd Hessling: German Cancer Research Center (DKFZ)
Karin Müller-Decker: German Cancer Research Center (DKFZ)
Gerrit Erdmann: NMI TT Pharmaservices
Elke Burgermeister: Heidelberg University
Matthias P. Ebert: Heidelberg University
Michael Boutros: German Cancer Research Center (DKFZ) and Heidelberg University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.

Date: 2019
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DOI: 10.1038/s41467-019-09898-0

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