Abstract P4-03-13: Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance

Abstract

The majority of breast cancer-specific deaths occur in women with recurrent, ERα (+), metastatic tumors that are initially responsive to endocrine therapy yet become endocrine-resistant. There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway profiling, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tamoxifen (4-OH-Tam) and Selinexor (SXR), a highly selective XPO1 inhibitor that is currently in clinical trials for leukemia and prostate cancer, inhibited Akt phosphorylation by changing the phosphorylation status and localization of the kinase. Since we observed dramatic changes in Akt activity, we hypothesized that metabolic pathways and consequently metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and induce autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for combined targeting of ERα and XPO1 in the clinic to reduce cancer recurrences. Citation Format: Madak Erdogan Z, Kulkoyluoglu E. Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-13.