ABSTRACT
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.
Subject(s)
Anilides/pharmacology , Drug Resistance, Neoplasm , Metabolome , Neoplasm Recurrence, Local/drug therapy , Oxadiazoles/pharmacology , Oxidative Phosphorylation/drug effects , Piperidines/pharmacology , Pyridines/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Animals , Apoptosis , Cell Proliferation , Drug Therapy, Combination , Female , Gene Expression Profiling , Genomics , Humans , Mice , Mice, Nude , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Counseling is an art learned over a lifetime, from other physicians during formal training and from one's personal counseling experiences. The effort to develop this art will be greatly appreciated and richly awarded with personal satisfaction. The importance of counseling and rehabilitation for the ocular trauma victim is in treating the whole patient, not only the injured eye. Every effort should be made to help a patient achieve a positive attitude about his or her capabilities to successfully use residual vision and live a full and enjoyable life as a visually impaired person.
