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 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.

Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

“…Mechanistically, the proliferation response is characterized by an expression signature that is enriched for genes involved in the G2/M checkpoint and DNA repair (Figure 2). On the one hand, this could indicate that WNT/CTNNB1 signaling operates to enhance DNA repair, as recently suggested (Kaur et al, 2021). On the other hand, it is tempting to speculate that this signature actually reflects replication stress.…”

“…This includes multiple E2F4 targets, such as Top2a and Aurkb, suggesting that their repression is relieved in response to enhanced WNT/CTNNB1 signaling (Figure 2E). Of note, the comparison of Wntlow and Wntmed expression profiles also revealed the induction of homologous recombination and Fanconi anemia pathway genes, such as Rad51, Brca1 and Fancd2 (Figure 2F), which were recently shown to be induced in WNT addicted cancers in a CTNNB1-and MYBL2/FOXM1 dependent manner (Kaur et al, 2021). Indeed, both Mybl2 and FoxM1 were upregulated in Wntmed organoids as well (Figure 2F), suggesting that the same mechanism might operate in direct response to elevated levels of WNT/CTNNB1 signaling.…”

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

“…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.…”

The multidimensional role of the Wnt/β‐catenin signaling pathway in human malignancies

“…Although mutations in the Wnt pathway guide us to determine prospective inhibitors, interference in Wnt signaling lacking mutations have been found to be effective in a hematopoietic cancer model, thus suggesting the aberrant activation of Wnt receptors as an effective oncogenic mechanism (Harmston et al, 2021; Kaur et al, 2021). Constitutive receptor activation might account for a hyperactive nonmutated Wnt signaling requiring a source of Wnt ligand; this source could either be the host itself or a cancer cell.…”