Oxidative phosphorylation is a metabolic vulnerability in chemotherapy-resistant triple negative breast cancer.

Abstract

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pre-treatment biopsies from patients with triple negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of an OXPHOS signature. In multiple TNBC patient-derived xenografts (PDXs), treatment with IACS-10759, a novel inhibitor of OXPHOS, stabilized tumor growth. Gene expression profiling revealed that all sensitive models displayed a basal-like 1 TNBC subtype, and expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen in tumors treated with IACS-10759 found several potential synthetic lethal targets, including CDK4. A combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 exhibited significant anti-tumor efficacy in vitro and in vivo. In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy compared to either single agent. Taken together, these data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.