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

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 in part via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also func

SUBMITTER: Kaur A 

PROVIDER: S-EPMC8033517 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature