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

// Anil Belur Nagaraj 1 , Peronne Joseph 1 , Olga Kovalenko 1 , Sareena Singh 2 , Amy Armstrong 2 , Raymond Redline 3 , Kimberly Resnick 2 , Kristine Zanotti 2 , Steven Waggoner 2 and Analisa DiFeo 1 1 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA 2 Department of Gynecology, Division of Gynecological Oncology, University Hospital Case Medical Center, Cleveland, OH, USA 3 Department of Pathology, University Hospital Case Medical Center, Cleveland, OH, USA Correspondence to: Analisa DiFeo, email: // Keywords :  patient derived xenograft, platinum resistance, tumor spheres, cancer initiating cells, β-catenin Received : April 23, 2015 Accepted : June 01, 2015 Published : June 29, 2015 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.