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

Journal Article (Journal Article)

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 in part 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.

Full Text

Duke Authors

Cited Authors

  • Kaur, A; Lim, JYS; Sepramaniam, S; Patnaik, S; Harmston, N; Lee, MA; Petretto, E; Virshup, DM; Madan, B

Published Date

  • April 9, 2021

Published In

Volume / Issue

  • 13 / 4

Start / End Page

  • e13349 -

PubMed ID

  • 33660437

Pubmed Central ID

  • PMC8033517

Electronic International Standard Serial Number (EISSN)

  • 1757-4684

Digital Object Identifier (DOI)

  • 10.15252/emmm.202013349

Language

  • eng

Conference Location

  • England