Abstract C016: Oxidative phosphorylation is a metabolic vulnerability in chemotherapy resistant triple negative breast cancer

There is a pressing need to identify improved therapies for triple negative breast cancers (TNBC) resistant to standard chemotherapy. To identify potential molecular targets, we performed RNA sequencing of pre-treatment biopsies from 43 patients with operable TNBC who received neoadjuvant anthracycline and taxane-based chemotherapy. Ingenuity pathway analysis demonstrated that the top canonical pathway associated with higher likelihood of recurrence was higher expression of oxidative phosphorylation (OXPHOS) signature. We therefore sought to determine the efficacy of IACS-10759, a potent inhibitor of OXPHOS, in 10 TNBC patient-derived xenografts (PDX), 8 generated from chemotherapy-resistant tumors. Partial response was observed in one PDX model and prolonged disease stabilization in 5 of 10 PDXs. PDXs with higher expression of protein coding mitochondrial genes were more sensitive to IACS-10759. AXL overexpression was associated with intrinsic and acquired IACS-10759 resistance. The combination of cabozantinib, a multi-kinase inhibitor targeting AXL, with IACS-10759 significantly improved responses in TNBC PDXs. In contrast, selective AXL inhibitor BGB324 or knockdown of AXL did not enhance IACS-10759 sensitivity. In addition, an in vivo synthetic lethality screen identified CDK4, PARP1 and PARP2 as potential combination targets for IACS-10759. Palbociclib as well as talazoparib enhanced growth inhibitory effect of OXPHOS inhibition in vitro and in vivo. Our data suggests that OXPHOS is a promising target in chemoresistant TNBC. IACS-10759 is currently in Phase 1 testing, including TNBC. Further work is needed to determine the optimal biomarker-driven combination partners. Citation Format: Kurt Evans, Stacy Moulder, Erkan Yuca, Stephen Scott, Natalia Paez Arango, Maryam Shariati, Christopher P Vellano, Turcin Saridogan, Xiaofeng Zheng, Ana Maria Gonzalez-Angulo, Ming Zhao, Xiaoping Su, Coya Tapia, Ken Chen, Argun Akcakanat, Charles M Perou, Bora Lim, Debu Tripathy, Timothy A Yap, Maria E Di Francesco, Giulio Draetta, Philip Jones, Joe Marszalek, Funda Meric-Bernstam. Oxidative phosphorylation is a metabolic vulnerability in chemotherapy resistant triple negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C016. doi:10.1158/1535-7163.TARG-19-C016