Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC ‐driven lymphoma

Abstract

MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC‐overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS‐010759. In a B‐lymphoid cell line, ectopic MYC activity and treatment with IACS‐010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro‐oxidant at high doses. In these conditions, ascorbate synergized with IACS‐010759 to kill MYC‐overexpressing cells in vitro and reinforced its therapeutic action against human B‐cell lymphoma xenografts. Hence, complex I inhibition and high‐dose ascorbate might improve the outcome of patients affected by high‐grade lymphomas and potentially other MYC‐driven cancers. image Deregulated expression of the oncogenic transcription factor MYC in B‐cell lymphoma induces a vulnerability to disruption of redox homeostasis by pharmacological treatment with the electron transport chain (ETC) complex I inhibitor IACS‐010759 and high‐dose ascorbate. MYC activation and IACS‐010759 treatment independently cause the buildup of reactive oxygen species (ROS), contributing to their synthetic‐lethal action in B‐cells. Glucose prevents IACS‐010759‐induced cell killing by sustaining the pentose phosphate pathway (PPP)‐dependent production of NADPH, which is then used to regenerate reduced glutathione (GSH), a major cellular antioxidant. High‐dose ascorbate augments IACS‐010759‐induced cell killing through an iron‐dependent pro‐oxidant activity. High‐dose ascorbate and IACS‐010759 show synergistic anti‐tumoral activity in pre‐clinical models of MYC‐driven B‐cell lymphomas.