WNT inhibition creates a BRCA-like state in Wnt-addicted cancer.
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.
['Kaur|Amanpreet|A|', 'Lim|Jun Yi Stanley|JYS|', 'Sepramaniam|Sugunavathi|S|', 'Patnaik|Siddhi|S|', 'Harmston|Nathan|N|', 'Lee|May Ann|MA|', 'Petretto|Enrico|E|', 'Virshup|David M|DM|0000-0001-6976-850X', 'Madan|Babita|B|0000-0003-1065-8589']
D000970:Antineoplastic Agents D045744:Cell Line, Tumor D004260:DNA Repair D009369:Neoplasms D000067856:Poly(ADP-ribose) Polymerase Inhibitors D060449:Wnt Signaling Pathway
homologous recombination BRCA1 FANCD2 DNA repair ETC-1922159