Abstract 4033: Combined MEK and BCL-2/XL inhibition as a potential drug combination for the treatment of high-grade serous ovarian cancer
Authors: Iavarone Claudia , Zervantonakis Ioannis , Selfors Laura M. , Palakurthi Sangeetha , Liu Joyce F. , Matulonis Ursula A. , Drapkin Ronny I. , Mills Gordon B. , Leverson Joel D. , Sampath Deepak , Brugge Joan S. 
Published: July 2017

Abstract
High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths. Despite an initial response to platinum-based chemotherapy, treatment resistance eventually occurs in most patients. The overall aim of our studies is to identify synergistic drug combinations for the treatment of HGSOC and biomarkers that predict sensitivity for future translation in clinical trials. In particular, this study focuses on the vulnerabilities of patient-derived ovarian cancer cells to combined inhibition of the MEK pathway and the anti-apoptotic proteins BCL-2 and BCL-XL.
The Ras/MAPK pathway is activated in a subset of HGSOC by gene copy alterations. However, MEK inhibitors have not been evaluated in HGSOC. In this study, we used a collection of 14 primary samples derived from ascites cells of platinum-resistant HGSOC patients (Liu JF et al. 2016). We investigated the sensitivity of these tumor cells to the MEK inhibitor cobimetinib (GDC-0973). Treatment with GDC-0973 had no effects on cell viability in vitro in any of the patient-derived models. To investigate the response to MEK inhibition, we performed Reverse Phase Protein Array of the tumor cells treated with 0.3μM of GDC-0973 in vitro. We found that MEK inhibition by GDC-0973 reduced cell cycle progression markers and upregulated the pro-apoptotic protein BIM. Since more than half of the models express high levels of anti-apoptotic BCL-2 family proteins which neutralize BIM, we examined the effects of antagonism of BCL-2 pro-survival proteins in combination with GDC-0973. Treatment with a combination of GDC-0973 and the BCL-2/XL antagonist, navitoclax (ABT-263) significantly reduced cell number and increased cell death in 10 out of 14 patient-derived models. Protein levels of BIM following treatment with GDC-0973 correlated with sensitivity to the drug combination (R2=0.8 p&lt;0.0001). Interestingly, the BIM levels after MEK inhibition correlate with BIM protein levels before the treatment, suggesting that baseline BIM levels could be used as biomarker of sensitivity. Levels of the pro-survival protein MCL-1 also played a critical role in patient-derived cells that were resistant to the drug combination. Indeed, treatment with a specific MCL-1 inhibitor, A-1210477, in combination with GDC-0973 and ABT-263 led to dramatic tumor cell killing in vitro compared to dual combination of GDC-0973 and ABT-263.
Finally, we tested the combination of GDC-0973 and ABT-263 in vivo and preliminary results indicate that the drug combination is well tolerated and is able to significantly reduce tumor growth in patient-derived xenograft models (n=4).
Our studies provide significant evidence that combined inhibition of MEK and BCL-2/XL may be an effective drug combination for treatment of HGSOC and that the pro-apoptotic protein BIM may serve as a predictive biomarker to stratify patients that can benefit from these targeted therapies
Citation Format: Claudia Iavarone, Ioannis Zervantonakis, Laura M. Selfors, Sangeetha Palakurthi, Joyce F. Liu, Ursula A. Matulonis, Ronny I. Drapkin, Gordon B. Mills, Joel D. Leverson, Deepak Sampath, Joan S. Brugge. Combined MEK and BCL-2/XL inhibition as a potential drug combination for the treatment of high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4033. doi:10.1158/1538-7445.AM2017-4033