Abstract 1636: The role of the ROR receptors in ovarian cancer progression and chemoresistance

Abstract

Abstract BACKGROUND: Despite recent advances in our understanding of the underlying genetic profile of distinct subtypes of ovarian cancer, overall survival remains poor. This is partly due to the absence of available targeted therapies, widespread metastatic disease at diagnosis, and the development of resistance to chemotherapy in the majority of patients. Patients with a more mesenchymal gene signature have a shorter overall survival, and are more likely to recur and develop chemoresistance. These patients also have upregulated Wnt signalling, a key developmental pathway associated with metastasis, epithelial to mesenchymal transition (EMT) and chemoresistance. AIM: To investigate the role of the novel Wnt receptors ROR1 and ROR2 in ovarian cancer progression and chemoresistance, to determine their feasibility as therapeutic targets. METHOD: Expression of ROR1 and ROR2 was measured in patient tumour (primary and metastatic) samples and ascites fluid taken at multiple time points during disease progression. In addition, the A2780 and cisplatin resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance. Profiling of EMT and Wnt genes was undertaken alongside cell proliferation, adhesion, migration, invasion and viability assays after modulation of ROR1 and ROR2. RESULTS: Expression of ROR1 and ROR2 is increased in ovarian cancer patients compared to benign fallopian tube and ovarian surface epithelium. High ROR1 expression is associated with type I epithelial ovarian cancer, and high ROR2 expression with aggressive type II epithelial ovarian cancer. Expression of each receptor fluctuates in paired metastatic samples compared to primary tumours, depending on the site of metastasis and recurrence time. Both receptors are increased in a model of cisplatin resistant ovarian cancer, and when silenced, cell migration and invasion is significantly inhibited. Silencing ROR1 and ROR2 also sensitizes resistant cells to cisplatin, and is associated with a shift away from a mesenchymal phenotype. CONCLUSION: Upregulation of ROR1 and ROR2 drives migration, invasion and chemoresistance through regulating EMT via β-catenin independent Wnt signalling. As cell surface regulators of β-catenin independent Wnt signalling, the ROR receptors represent potential therapeutic targets for chemoresistant cancers. Citation Format: Claire E. Henry, Estelle Llamosas, Neville F. Hacker, Viola Heinzelmann-Schwarz, Caroline E. Ford. The role of the ROR receptors in ovarian cancer progression and chemoresistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1636.