Activation of Wnt signaling promotes olaparib resistant ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) has one of the highest death to incidence ratios among all cancers. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype due to the lack of therapeutic options following debulking surgery and platinum/taxane‐based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)‐ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair‐deficient (HRD) HGSOCs, recent studies have observed a significant benefit in non‐HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance. Therefore, there is an urgent clinical need to understand PARPi resistance and to introduce novel combinatorial therapies to manage PARPi resistance and extend HGSOC disease‐free intervals. In a panel of HGSOC cell lines, we established matched olaparib sensitive and resistant cells. Transcriptome analysis of the matched olaparib‐sensitive vs ‐resistant cells revealed activation of the Wnt signaling pathway and consequently increased TCF transcriptional activity in PARPi‐resistant cells. Forced activation of canonical Wnt signaling in several PARPi‐sensitive cells via WNT3A reduced olaparib and rucaparib sensitivity. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA‐approved compound, pyrvinium pamoate, which has been shown to promote downregulation of β‐catenin. In both an HGSOC cell line and a patient‐derived xenograft model, we observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARP and Wnt inhibitors.

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

“…Other studies have also suggested Wnt signaling drives enhanced DNA repair. Sun et al identified WNT16B as a driver of resistance to cytotoxic chemotherapy in prostate cancer (66) while Yamamoto et al identified WNT3A expression as the cause of in vitro olaparib resistance in an ovarian cancer cell (67). Here we find that Wnts regulate the expression of HR and FA pathway genes in part via a β-catenin/MYBL2 axis.…”

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

“…Supporting these results, in non-small cell lung cancer it has been shown that maintaining the lung cancer stem cell population requires the degradation of the WNT negative regulators, increasing β-catenin mediated WNT activity (77). Furthermore, WNT signaling plays a critical role in the maintenance and propagation of ovarian cancer stem cells (78); it is critical in desmoid tumor formation (79), and in head and neck squamous carcinomas (HNSCC), where researchers have shown CSC elimination after WNT/β-catenin signaling was downregulated.…”

Wnt Signaling and Drug Resistance in Cancer

“…Although this protective effect has been attributed to the downstream effectors of Wnt/b-catenin signaling such as survivin in one study, more generally the underlining mechanism still remains unclear (Watson et al, 2010;Gao et al, 2013;Nagano et al, 2013;Emons et al, 2017). Two recent studies found that elevated Wnt signaling enhanced the DNA damage repair and thereby conferred resistance to the PARP inhibitor olaparib in ovarian cancers (Fukumoto et al, 2019;Yamamoto et al, 2019). This mechanism could also protect cancer cells from DNA damage caused by other conventional chemo agents or radiation.…”

“…Wnt/b-catenin signaling mediated resistance to PARP inhibition in ovarian cancer due in part to upregulation of DNA damage repair. Inhibition of b-catenin signaling reverted resistance to olaparib in ovarian cancer xenografts (Fukumoto et al, 2019;Yamamoto et al, 2019). Vismodegib (Hedgehog signaling inhibitor)…”