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

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 i...

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Detalles Bibliográficos
Autores principales: Zhan, Tianzuo, Ambrosi, Giulia, Wandmacher, Anna Maxi, Rauscher, Benedikt, Betge, Johannes, Rindtorff, Niklas, Häussler, Ragna S., Hinsenkamp, Isabel, Bamberg, Leonhard, Hessling, Bernd, Müller-Decker, Karin, Erdmann, Gerrit, Burgermeister, Elke, Ebert, Matthias P., Boutros, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522484/
https://www.ncbi.nlm.nih.gov/pubmed/31097693
http://dx.doi.org/10.1038/s41467-019-09898-0
Descripción
Sumario: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.