Abstract 208: BPM 31510-induced alteration in Complex II activity is functionally linked to cell death activation pathway in a preclinical model of triple-negative breast cancer

Although only 15-20% of total breast cancer diagnoses are of the triple-negative breast cancer (TNBC) subtype, they account for a significant portion of the mortality rate due to their more aggressive phenotype and a high risk of reoccurrence. Metabolic rewiring supports breast cancer progression and metastasis, particularly in ER-negative and triple-negative (TNBC) breast tumors. Thus, we examined the effects of BPM 31510, a metabolic-modulating agent in clinical trials for solid tumors, in in vitro and in vivo ER-negative and TNBC models. BPM 31510 EC50/EC>90 values were determined for a panel of the breast cancer cell lines and compared to non-tumorigenic MCF12A cells in vitro, and the MDA-MB231 and SkBr-3, TNBC and ER-negative models respectively, were found to be the most sensitive to BPM 31510. Treatment with BPM 31510 (EC50 and EC>90 doses) resulted in a time- and dose-dependent decrease the viable cell population (PI- and Annexin V-negative) and a concomitant increase in cells in early and late apoptosis (PI-negative and PI-positive Annexin V-positive cells, respectively), suggesting that BPM 31510 activates regulated cell death pathways. Consistent with the in vitro data, MDA-MB231 tumor-bearing mice had smaller tumors after 30 days of treatment with BPM 31510 and increased cleaved caspase 3 staining in resected tumors. In vitro, BPM 31510-dependent breast cancer cell death was preceded by mitochondrial membrane potential depolarization (TMRE flow cytometry) and alterations in mitochondrial respiration characterized by a consistent, dose-dependent decrease in succinate (Complex II)-fueled respiration with more varied responses to BPM 31510 in cells provided the Complex I substrates (pyruvate or palmitoyl carnitine). To investigate the role of Complex II in BPM 31510-mediated cell death, pharmacological inhibitors of the dicarboxylate site (malonate) and Qp site (atpenin A5) of Complex II were used in combination with BPM 31510 to assess the resultant effects on cell death in MDA-MB231 cells. Co-treatment with malonate significantly attenuated BPM 31510-mediated cell death while atpenin A5 did not affect BPM 31510-induced cell death, indicating succinate oxidation at the dicarboxylate site of Complex II is required, in part, for induction of cell death by BPM 31510. Together, these data demonstrate BPM 31510 has a potent anti-cancer activity in preclinical breast cancer models and define a functional link between Complex II activity and the mechanism of action for BPM 31510. Citation Format: Tulin Dadali, Anne R. Diers, Arleide Lee, Ezer Benaim, Joaquin J. Jimenez, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510-induced alteration in Complex II activity is functionally linked to cell death activation pathway in a preclinical model of triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 208.