Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cance
Additional Publication URL
Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment 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 OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.
This open access article is distributed under Creative Commons Attribution NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND). The article of record can be found at Cancer Research.
Evans, Kurt W.; Yuca, Erkan; Scott, Stephen S.; Zhao, Ming; Paez Arango, Natalia; Cruz Pico, Christian X.; Saridogan, Turcin; Shariati, Maryam; Class, Caleb; Bristow, Christopher A.; Vellano, Christopher P.; Zheng, Xiaofeng; Gonzalez-Angulo, Ana Maria; Su, Xiaoping; Tapia, Coya; Chen, Ken; Akcakanat, Argun; Lim, Bora; Tripathy, Debu; Yap, Timothy A.; Di Francesco, Maria Emilia; Draetta, Giulio F.; Jones, Philip; Heffernan, Heffernan P.; Marszalek, Joseph R.; and Meric-Bernstam, Funda, "Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cance" (2021). Scholarship and Professional Work – COPHS. 293.