Journal
CANCER RESEARCH
Volume 81, Issue 21, Pages 5572-5581Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-3242
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Funding
- NCI PDX Development and Trial Center U54 [CA224065]
- NIH [T32 CA009599]
- MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer
- MDAnderson Breast Cancer Moonshot Program
- NIH Clinical Translational Science Award [1UL1TR003167]
- Nellie B. Connally Breast Cancer Research Endowment
- Cancer Prevention & Research Institute of Texas [RP180248]
- MD Anderson Cancer Center Support Grant [P30 CA016672]
- Barr funds
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Oxidative phosphorylation is a metabolic vulnerability in triple-negative breast cancer, and inhibiting it with IACS-10759 may enhance efficacy of multiple targeted therapies.
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.
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