WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Kaur, Amanpreet, Sepramaniam, Sugunavathi, Lim, Jun Yi Stanley, Patnaik, Siddhi, Harmston, Nathan, Lee, May Ann, Petretto, Enrico, Virshup, David M. and Madan, Babita 2020. WNT inhibition creates a BRCA-like state in Wnt-addicted cancer. [Online]. bioRXiv: bioRXiv. Available at: https://doi.org/10.1101/2020.06.17.157024

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Abstract

Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51 are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APCmin mutant polyps. Our findings suggest a general paradigm that Wnt/β-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.

Item Type:	Website Content
Date Type:	Submission
Status:	Published
Schools:	Biosciences
Publisher:	bioRXiv
Last Modified:	24 Aug 2023 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/161866

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