Abstract 949: miR-634 restores drug sensitivity in tumor cells derived from patients with terminal drug-resistant ovarian cancer.

Abstract

Abstract The development of drug resistance is still a major impediment for the successful treatment of cancer. This is particularly pressing in the case of advanced ovarian cancer, which has a 5-year survival rate of 30%. Ovarian cancer is treated with paclitaxel and platinum (e.g cisplatin or carboplatin) combination chemotherapy. Despite an initial high chemo-responsiveness, most ovarian cancer patients will relapse and ultimately die of drug-resistant disease. The molecular processes that contribute to resistance have been extensively studied, however, not much is known about the role of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression. We compared miRNA expression profiles of isogenic cisplatin sensitive and resistant cell line pairs. The only miRNA that was consistently downregulated in all three resistant cell lines was miR-634 (FDR<1%). Overexpression of miR-634 in ovarian cancer cell lines gave rise to a minor, but reproducible, cell cycle block and reduced cellular viability by 20-50%. In addition, miR-634 transfection resensitized cisplatin-resistant ovarian cancer cell lines. We next investigated whether miR-634 overexpression could enhance therapy response in a more clinical setting. We isolated and cultured tumor cells from 7 patients that had become refractory to carboplatin-paclitaxel combination chemotherapy. We show that miR-634 overexpression causes a ∼two-fold decrease in IC50 for cisplatin and carboplatin treatment. In addition, a ∼1.3-fold decrease in doxorubicin sensitivity was observed upon miR-634 overexpression. Finally, overexpression of miR-634 resulted in downregulation of its predicted targets Cyclin D1 and GRB2, ERK2, RSK1 and RSK2, components of the Ras-MAPK pathway. The combined effect on these miR-634 targets may explain the effects on the cell cycle, cellular viability and response to chemotherapy. Altogether, our findings suggest that miR-634 modulates important cancer relevant targets and that raising miR-634 levels can be a means to resensitize chemotherapy resistant ovarian tumors. Citation Format: Marijn TM van Jaarsveld, Patricia F. van Kuijk, Antonius WM Boersma, Jozien Helleman, Wilfred F. van Ijcken, Ron HJ Mathijssen, Joris Pothof, Els MJJ Berns, Jaap Verweij, Erik AC Wiemer. miR-634 restores drug sensitivity in tumor cells derived from patients with terminal drug-resistant ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 949. doi:10.1158/1538-7445.AM2013-949