Abstract A37: Combined targeting of estrogen receptor alpha and nuclear transport pathways remodels metabolic pathways to induce apoptosis and overcome tamoxifen resistance

Majority of breast cancer specific deaths occur in women with recurrent, ERα (+), metastatic tumors that are endocrine therapy resistant. There is a critical need for novel therapeutic approaches to resensitize 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 Cignalfinder pathway profiling, Seahorse metabolic profiling, and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tam and selinexor (SXR), an XPO1 antagonist being evaluated in multiple later-stage clinical trials in patients with relapsed and /or refractory hematologic and solid tumor malignancies, inhibited Akt phosphorylation by changing the localization of the kinase. Since we observed dramatic changes in Akt activity, we hypothesized that glucose utilization 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. In order to examine metabolites that might result in the observed phenotype, we performed whole metabolite profiling and identified proline metabolic pathways to be upregulated when cells were treated with SXR+4-OH-Tam. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways, increases demand on mitochondria, and causes increased production of ROS that would eventually lead to apoptosis. 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 uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences. Citation Format: Eylem Kulkoyluoglu Cotul, Kinga Wrobel, Landesman Yosef, Zeynep Madak-Erdogan. Combined targeting of estrogen receptor alpha and nuclear transport pathways remodels metabolic pathways to induce apoptosis and overcome tamoxifen resistance [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A37.