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 30 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 APC min mutant polyps. Our findings suggest a general paradigm that Wnt/β-40 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. 610

Single Cell Transcriptomics identifies a WNT7A-FZD5 Signaling Axis that maintains Fallopian Tube Stem Cells in Patient-derived Organoids

“…Along with inhibiting WβS, we note Estrogen suppresses BRCA1 and BRCA2 expression in hFT organoids, possibly through MYBL2 (Figure S9I) as reported (Kaur et al, 2021). This is phenocopied by Estrogenindependent WNT inhibition (Figure S9I), suggesting Estrogen regulates BRCA1/2 expression, at least in part, through regulating WβS.…”

“…Finally, WβS was recently shown to regulate the expression of DNA double-strand break repair genes, including BRCA1, BRCA2, RAD51 and the FANC gene family, in various tissues (Kaur et al ., 2021; Angers, 2021). Along with inhibiting WβS, we note Estrogen suppresses BRCA1 and BRCA2 expression in hFT organoids, possibly through MYBL2 (Figure S9I) as reported (Kaur et al ., 2021). This is phenocopied by Estrogen-independent WNT inhibition (Figure S9I), suggesting Estrogen regulates BRCA1/2 expression, at least in part, through regulating WβS.…”

“…In this regard, one hypothesis we propose is that WβA cells possess enhanced self-renewal capacity and may be primed to be the targets of early HGSOC-initiating mutations that produce precursor STIC lesions, which subsequently progress to advanced HGSOCs that retain the expression of these markers. Furthermore, recent studies show that WβS regulates expression of DNA double-strand break repair genes via a WβS/MYBL2 signaling axis (Kaur et al ., 2021; Angers, 2021). This includes BRCA1 and BRCA2 genes, which are of clinical relevance to HGSOC initiation.…”

“…Finally, WβS was recently shown to regulate the expression of DNA double-strand break repair genes, including BRCA1, BRCA2, RAD51 and the FANC gene family, in various tissues (Kaur et al, 2021;Angers, 2021).…”

Wnt signaling inhibition confers induced synthetic lethality to PARP inhibitors

“…In this issue of EMBO Molecular Medicine , Kaur et al (2021) performed a chemical screen to identify genes that synergize with Porcupine inhibitors in Wnt‐addicted cancers. The combination of the PARP inhibitor olaparib with the Porcupine inhibitor ETC‐159 revealed robust synergy in inhibiting the growth of various Wnt‐addicted cancer cell lines harboring mutations in RNF43 or R‐spondin fusion.…”