Abstract PR01: Adaptive resistance of patient-derived ovarian cancer cells to PI3K/mTOR inhibition

Abstract

Abstract Relapse due to drug resistance remains a major challenge for successful cancer treatment despite advances in chemotherapy efficacy and the development of targeted therapies. We have previously reported a therapy-induced adaptive response that is associated with treatment resistance and are investigating whether this adaptive response program could be targeted to increase treatment efficacy (Muranen et al, Cancer Cell 2012). The PI3K pathway is amplified in high-grade serous ovarian tumor and represents an attractive target in this cancer subtype. We found that both in vitro and in vivo exposure of patient-derived ovarian cancer cells to the PI3K/mTOR dual inhibitor GNE-493 increases the levels of the anti-apoptotic Bcl-2 protein, and multiple tyrosine kinase receptors, such as EGFR and HER2. Concurrent treatment of these cancer cells with GNE-493 and ABT737 (a Bcl-2 and Bcl-xl dual inhibitor) causes a reduction in cell number and increased cell death. Ongoing studies are underway to comprehensively characterize the adaptive response signature of a panel of patient-derived ovarian cancer cells and study whether targeting multiple different upregulated proteins (e.g. EGFR) may increase PI3K/mTOR treatment efficacy. Therapy resistance has also been associated with exposure of tumor cells to pro-survival factors secreted by supporting cells in the tumor microenvironment (Straussman et al, Nature 2012 and Wilson et al, Nature 2012). We found that the growth-factors EGF, inflammatory cytokine IL-6 and ascites fluid from ovarian cancer patients induces up-regulation of Bcl-2 as well as IGFR, which masked the adaptive response to PI3K/mTOR inhibitors. We are performing ongoing studies using orthotopic patient-derived ovarian cancer xenografts to investigate the patterns of residual disease in vivo with the ultimate goal to identify whether Bcl-2 targeted drugs will enhance the efficacy of PI3K/mTOR inhibition and whether there is differential sensitivity at distinct anatomical sites (pancreas, diaphragm, peritoneal wall). Our studies provide a framework to identify adaptive response programs and tumor microenvironment factors in patient-derived ovarian cancer cells that limit treatment efficacy of PI3K/mTOR pathway inhibition and to develop therapies to abrogate this resistance. Citation Format: Ioannis Zervantonakis, Hsing-Yu Chen, Taru Muranen, Joyce Liu, Ronny Drapkin, Ursula Matulonis, Joan Brugge. Adaptive resistance of patient-derived ovarian cancer cells to PI3K/mTOR inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR01.