Abstract 1749: Cell cycle requirements shape ovarian cancer progression.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Acquired resistance to chemotherapeutic drugs and subsequent recurrence of drug-resistant cancer are serious challenges associated with epithelial ovarian cancer. Most high-grade tumors initially respond well to the combination of platinum and taxane-based agents but recur as platinum-resistant disease, which is incurable. In addition, a subset of primary tumors, including CCNE1-amplified tumors, are inherently less susceptible to standard chemotherapy. Studies by The Cancer Genome Atlas have revealed that CCNE1 (cyclin E) amplification is mutually exclusive with mutations in BRCA1 and BRCA2, which render ovarian cancer cells sensitive to DNA-damaging agents and PARP inhibitors, as a result of synthetic lethality. In order to develop a similar therapeutic concept for CCNE1-amplified cancers, we have studied responses and resistance mechanisms of human ovarian cancer cells to several pharmacological inhibitors of cyclin-dependent kinases (CDK). Functional and biochemical studies have established cyclin E as an activator of CDK, which phosphorylate the RB tumor suppressor. However, despite the functional importance of the RB pathway in cancer, CDK inhibitors (CDKi) have yet to make a significant impact on the management of solid tumors. Here, we describe oncogenic pathways that are activated in CDKi-resistant cells and play critical roles in tumor progression and drug resistance. Targeting individual CDK or subsets of multiple CDK in vitro and in vivo, we found that cyclin E dependence was the main driving force that shaped tumor progression in different model systems of CCNE1-amplified and recurrent ovarian cancer. We identified robust and specific compensatory mechanisms that sustain cyclin E-associated activity in CDKi-resistant cells via activation of oncogenic signaling upstream of the cyclin E-RB-E2F axis. Specific targeting of cooperating oncogenes increased CDKi efficacy and prevented the outgrowth of CDKi-resistant cancer cells. Collectively, our results suggest that CDKi can be highly effective elements of combination therapy. Citation Format: Barbie Taylor-Harding, Hasmik Agadjanian, Sandra Orsulic, Christine Walsh, Beth Y. Karlan, Wolf-Ruprecht Wiedemeyer. Cell cycle requirements shape ovarian cancer progression. [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 1749. doi:10.1158/1538-7445.AM2013-1749