Targeting the bioenergetics of a resistant tumor: clinical insights into OXPHOS inhibition for cancer therapy

Although a century has passed since Otto Warburg's discovery of the glycolytic pathway of energy production by many malignant tumors compared to normal tissues, current data cast doubt on the universality of this hypothesis. In particular, numerous recent papers suggest that in response to chemotherapy or radiotherapy, many malignant tumors prefer to activate mitochondrial oxidative phosphorylation (OXPHOS). Moreover, data from many laboratories, including our own, show that OXPHOS and related redox proteins are preferential metabolic pathways for resistant tumors and cells, and therefore may be targeted specifically in cases of tumor relapse. This work aims to provide an overview of the use of OXPHOS inhibition as an alternative therapy approach for resistant tumors and includes a description of the confirmed key mechanisms and the results of clinical trials of OXPHOS inhibitors and possible side effects arising therefrom. We mainly discuss original papers and clinical trials published in the past 5-7 years.