Abstract 4139: Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis relative to other breast cancers. Due to its lack of expression of commonly targeted cell surface markers and hormone receptors, there is a dearth of precision treatment options for this malignancy, with chemotherapy and radiation therapy remaining the major mainstays of care. Our group has previously reported that the receptor tyrosine kinase EphA2 is enriched in the basal-like/triple-negative breast cancer subtype and that this expression is associated with reduced recurrence-free survival. Furthermore, genetic knockdown or inhibition of EphA2 with the small molecule ALW-II-41-27 (ALW) reduces cancer cell growth in vitro and in vivo. In these studies, we sought to investigate whether the antitumor properties of ALW can be augmented by addition of other compounds to further reduce cancer cell growth and induce apoptosis. To this end, TNBC lines MDA-MB-231, BT-549, HCC1395, and HCC1187 were seeded in 96-well plates and exposed to ALW alone or in combination with chemotherapeutic agents doxorubicin and paclitaxel, CDK inhibitor SCH-727965, and MCL-1 inhibitor S63845 and cell viability assessed by MTT assay at 48 hours. While there was no significant reduction in viability for cells treated with ALW plus chemotherapy and no consistent improvement with addition of S63845 across cell lines, the combination of ALW with SCH-727965 performed significantly better than either drug alone (p < 0.05) in HCC1395 and BT-549 cells. To evaluate drug synergy, cells of all lines above were exposed to variable concentrations of SCH-727965, ALW, and the combination in a fixed ratio of their respective IC50 values to generate dose response curves, and these data analyzed via CompuSyn software. Combination indices (CI) were <1 for the majority of conditions across all cell lines, supporting synergistic interaction. Effects were most pronounced in HCC1395 cells with average CI 0.82. Furthermore, TUNEL assays show that addition of SCH-727965 to ALW significantly increases the induction of apoptosis by HCC1395 and HCC1187 cells. These preclinical studies demonstrate that combination of ALW and SCH-727965 potently reduces TNBC cell growth and promotes cell death, representing promising early data on the effects of EphA2 inhibition as part of a combination targeted therapeutic approach for triple-negative breast cancer. Citation Format: Kalin L. Wilson, Dana M. Brantley-Sieders. Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4139.