In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment

SIMPLE SUMMARY: The vast majority of tumors originate in tissues that use different substrates and oxygen to produce energy. However, tumors are disorganized structurally and functionally, which creates areas where oxygen and nutrients are poorly available. To survive and proliferate, cancer cells adapt by switching their metabolism to lactic fermentation. Their fate is further optimized by intercellular cooperation, but this creates a weakness that can be exploited therapeutically. Indeed, AZD3965 is a new drug currently tested in clinical trials that inhibits a cooperation based on lactate swapping for glucose between fermenting and respiring cells. It inhibits lactate transporter monocarboxylate transporter 1. Here, using malignant and nonmalignant cells representative of the breast tissue and several behavioral tests in mice, we establish that AZD3965 is safe for therapeutic use against cancer. The only side effect that we detected was a short-term memory retention defect that transiently perturbed the orientation of mice in space. ABSTRACT: To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy.