OXPHOS inhibition overcomes chemoresistance in triple negative breast cancer

Abstract

The hypothesis of a significant shift from oxidative phosphorylation (OXPHOS) to glycolysis in a number of solid tumors has been dominant for many years. Recently, however, evidence has begun to accumulate that OXPHOS is the major mode of energy production in many neoplasias, especially those that have undergone chemo- or radiotherapy, and especially in chemoresistant malignancies. In the present work, we demonstrated that chemoresistant triple-negative breast cancer cells prefer to obtain energy via OXPHOS to a greater extent than cells sensitive to chemotherapeutic agents, and therefore the former can be affected by some OXPHOS inhibitors. From a drug library containing several dozen antimicrobials, we selected those that inhibit OXPHOS in resistant TNBC cells and lead to mitochondrial dysfunction. We have also identified several pathways by which inhibition of growth suppression of chemoresistant cells occurs, including increased oxidative stress and mitophagy. Experiments in mice showed that selected OXPHOS inhibitors preferentially suppress tumor growth from chemoresistant but not from chemosensitive cells. The results of the present study suggest combinatorial therapy of such inhibitors and conventional anticancer drugs on resistant forms of tumors, if the latter show enhanced OXPHOS. • Breast cancer patients with elevated OXPHOS have an unfavorable clinical prognosis. • Chemoresistant breast tumors have elevated mitochondrial OXPHOS gene expression. • OXPHOS inhibitors as antimicrobials suppress chemoresistant tumors in vivo. • Anticancer mechanisms involve mitochondrial dysfunction via oxidative stress and mitophagy. • Combination of OXPHOS inhibitors with chemotherapeutic drugs overcomes their resistance.

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