title: 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.
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Anil Belur
authors.initials: AB
authors.lastname: Nagaraj
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Peronne
authors.initials: P
authors.lastname: Joseph
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Kovalenko
authors.affiliation: Department of Gynecology, Division of Gynecological Oncology, University Hospital Case Medical Center, Cleveland, OH, USA.
authors.forename: Sareena
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Gynecology, Division of Gynecological Oncology, University Hospital Case Medical Center, Cleveland, OH, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Armstrong
authors.affiliation: Department of Pathology, University Hospital Case Medical Center, Cleveland, OH, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Redline
authors.affiliation: Department of Gynecology, Division of Gynecological Oncology, University Hospital Case Medical Center, Cleveland, OH, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Resnick
authors.affiliation: Department of Gynecology, Division of Gynecological Oncology, University Hospital Case Medical Center, Cleveland, OH, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Zanotti
authors.affiliation: Department of Gynecology, Division of Gynecological Oncology, University Hospital Case Medical Center, Cleveland, OH, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Waggoner
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Analisa
authors.initials: A
authors.lastname: DiFeo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011744:Pyrimidinones / Q000494:pharmacology; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D051153:Wnt Proteins; D051176:beta Catenin; D002945:Cisplatin
keywords: cancer initiating cells; patient derived xenograft; platinum resistance; tumor spheres; β-catenin