Abstract 4804: Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC), although accounting for 15-20% of breast cancer, is disproportionally responsible for female cancer death. Despite therapeutic strategies being advanced, the clinical outcome of mTOR-targeted chemotherapy remains poor in the past decades. Recent data have evidenced the interdependence of kinase signaling networks and their involvement in treatment refractory TNBC settings. Thus, a combinatorial therapy targeting multiple components of signaling cascade is urgently needed. We assessed drug response phenotype across 20 TNBC cell lines by profiling the effect of a kinase inhibitor library consisting of >350 different kinase inhibitors (KIs). A panel of TNBC cell lines clustered with resistance phenotype against rapalogues (rapamycin analogues). Rapamycin efficacy on TNBCs was detected by performing proliferation assays and calculating their IC50, respectively. Given the role of the mTOR pathway in translational control, the relationship between rapamycin responses (IC50) and translational factors expression in TNBC cell lines was studied by Pearson analysis. Notably, translation initiation factor EIF2B2, EIF2S3, EIF3S8 and EIF1AX positively correlated with rapamycin response, whereas EIF4EBP2 and EIF2AK2 displayed negative correlation. Next, a rapamycin combination KI library screen was performed to identify kinase inhibitors synergizing with mTOR inhibition. AEE788, a multiple kinase targeting inhibitor, synergistically enhanced inhibitory effect of rapamycin on TNBC cell proliferation. Moreover, AEE788 dose-dependently synergized with mTOR targeted therapy in several TNBC cell lines. The combination treatment significantly decreased phosphorylation level of mTOR and 4EBP1 as well as ERK, indicating downregulation of PI3K/AKT and MAPK pathways. ChEMBL-based cheminformatics analysis indicated that, besides VEGFR and EGFR, a number of other kinases were predicted as the targets of AEE788, including RPS6K1, AKT2 and CDK7. Altogether, our data reveals the essential role of rapamycin-associated translation factors in TNBC, and provides insight in the resistance of TNBC to rapamycin analogues as well as potential therapeutic approaches to alleviate rapamycin resistance. Citation Format: Jichao He, Ronan P. McLaughlin, Vera van der Noord, Gerard van Westen, Yinghui Zhang, Bob van de Water. Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4804.