Format

Send to

Choose Destination
Nat Commun. 2019 May 16;10(1):2197. doi: 10.1038/s41467-019-09898-0.

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

Author information

1
Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, 69120, Heidelberg, Germany.
2
Department of Internal Medicine II of the Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
3
NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770, Reutlingen, Germany.
4
Proteomics Core Facility, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
5
Core Facility Tumor Models, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
6
NMI TT Pharmaservices, 13353, Berlin, Germany.
7
Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, 69120, Heidelberg, Germany. m.boutros@dkfz.de.

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.

PMID:
31097693
PMCID:
PMC6522484
DOI:
10.1038/s41467-019-09898-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center