Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance

Abstract

Resistance to platinum-based chemotherapy is the major barrier to treating epithelial ovarian cancer. To improve patient outcomes, it is critical to identify the underlying mechanisms that promote platinum resistance. Emerging evidence supports the concept that platinum-based therapies are able to eliminate the bulk of differentiated cancer cells, but are unable to eliminate cancer initiating cells (CIC). To date, the relevant pathways that regulate ovarian CICs remain elusive. Several correlative studies have shown that Wnt/β-catenin pathway activation is associated with poor outcomes in patients with high-grade serous ovarian cancer (HGSOC). However, the functional relevance of these findings remain to be delineated. We have uncovered that Wnt/β-catenin pathway activation is a critical driver of HGSOC chemotherapy resistance, and targeted inhibition of this pathway, which eliminates CICs, represents a novel and effective treatment for chemoresistant HGSOC. Here we show that Wnt/β-catenin signaling is activated in ovarian CICs, and targeted inhibition of β-catenin potently sensitized cells to cisplatin and decreased CIC tumor sphere formation. Furthermore, the Wnt/β-catenin specific inhibitor iCG-001 potently sensitized cells to cisplatin and decreased stem-cell frequency in platinum resistant cells. Taken together, our data is the first report providing evidence that the Wnt/β-catenin signaling pathway maintains stem-like properties and drug resistance of primary HGSOC PDX derived platinum resistant models, and therapeutic targeting of this pathway with iCG-001/PRI-724, which has been shown to be well tolerated in Phase I trials, may be an effective treatment option.

Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer

“…Our data using activators and inhibitors of Wnt signaling support an inverse correlation between Wnt activation and platinum sensitivity. Our data are consistent with reports suggesting inhibition of Wnt target genes after platinum therapy [38], but dissimilar to studies supporting Wnt inhibition as a modality or re-sensitizing OC to platinum [39]. The distinct cell models and experimental conditions (selection of platinum resistant tumors in vivo vs. in vitro , different doses of inhibitors) may account for the observed differences.…”

Altered glutamine metabolism in platinum resistant ovarian cancer

“…We evaluated two paired cell lines: the cisplatin sensitive A2780 cell line and its cisplatin resistant derivative CP70, together with the cisplatin sensitive OV81.2 cell line, which is a primary cell line derived from a high grade serous ovarian cancer patient. The cisplatin resistant derivative OV81.2-CP10 (referred to as CP10 henceforth) was derived by propagating OV81.2 cells in the presence of cisplatin for 10 passages thus selecting for resistant clones [24]. …”

“…This is often related to reduced platinum accumulation in ovarian cancer cells, linked to increased expression of multidrug resistance associated transporters [29]. In ovarian cancer, platinum resistance has also been associated with an increase in stem-like properties mediated by upregulated Wnt signaling [24] and differential expression of microRNAs such as miR-181a [30]. More recently several studies have highlighted the importance of altered glucose or fatty acid metabolism in mediating resistance to chemotherapy or targeted therapies [31–38].…”

Genetic variants of lncRNA HOTAIR and risk of epithelial ovarian cancer among Chinese women

“…It's reported that there will be totally 21,290 new cases and 14,180 new deaths in United States in 2015 [1]. Epithelial ovarian cancer (EOC) accounts for 90% to 95% of all cases of ovarian cancer [2, 3]. However, the etiology of EOC is not well understood but is likely to involve both genetic and environmental factors [4].…”