Abstract 738: Targeting metabolic vulnerabilities of endocrine resistant breast cancers using XPO1 and NAMPT inhibition

Abstract

Abstract Introduction: Approximately 70% of human breast cancers express estrogen receptor alpha (ERα), providing the potential for targeted endocrine therapy for patients. Unfortunately, 30-40% of ER+ patients still experience recurrence and metastasis with a 5-year relative overall survival rate of just 24%. Previously, we described metabolic changes in metastatic breast cancer cells that are driven by single therapies and the metastatic organ microenvironment. Combining selinexor (SEL), a small molecule inhibitor of exportin 1 (XPO1) approved by the FDA for treatment of some hematologic malignancies, with the current therapies used for advanced breast cancers (e.g. tamoxifen) decreased metabolic adaptations in response to individual drug treatments and prevented colony formation in hydrogels and tumor growth in xenograft models. Since we observed a reliance on NAD+ metabolism in cancer cells that are treated with single therapies, in the current study we investigated co-targeting metabolic alterations using SEL and the NAMPT inhibitor KPT-9274. Methods: We established 3D cell culture systems in novel hydrogels derived from decellularized bone, lung, and liver tissues - the major sites of metastasis of ER+ breast cancers, and compared with standard Matrigel culture. Endocrine responsive (MCF7 and T47D) and resistant (MCF7 and T47D cells with ESR1 Y537S or D538G mutations) breast cancer cell lines were treated with SEL or KPT-9274. Tumorigenicity was assessed using in vitro cell viability and colony formation assays and in vivo breast cancer cell line xenografts in athymic mice. Metabolic changes were assessed using whole metabolite profiling by GC-MS and a Seahorse XF analyzer. Results: Combining an FDA-approved XPO1 small molecule inhibitor, Selinexor (SEL) with the NAMPT inhibitors decreased metabolic adaptations in response to individual drug treatments, and prevented colony formation in hydrogels and tumor growth in xenograft models. Conclusions: Targeting drug and metastatic-site induced adaptations to regenerate new vulnerabilities in endocrine-resistant breast tumors are novel. Given the need for better strategies for improving therapy response of metastatic ER+ tumors, our findings show uncovering the role XPO1-NAMPT crosstalk plays in metastatic breast cancer could lead to new combined therapies that reduce mortality. Citation Format: Qianying Zuo, Ayca Mogol, Ozan Imir, Yosef Landesman, Zeynep Madak Erdogan. Targeting metabolic vulnerabilities of endocrine resistant breast cancers using XPO1 and NAMPT inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 738.