Targeting the Hypoxic Fraction of Head and Neck Squamous Cell Carcinoma through the Inhibition of Lactate Transporters MCT1 and MCT4 in Synergy with Metformin

Abstract

Head and neck cancer is a common form of cancer, and a major factor affecting treatment outcome is tumour hypoxia. A defining characteristic of hypoxia are the changes in cellular metabolism such as producing large amounts of lactate. Monocarboxylate transporters (MCTs) play a crucial role in regulating lactate metabolism, and thus constitute a target against hypoxic cells. In this study, we explored the possibility of inhibiting MCT1 and MCT4 in conjunction with the antidiabetic drug metformin to selectively kill hypoxic cells. We generated a double MCT1/4 knockout cell line and have shown this strategy is effective in halting HNSCC cell proliferation under hypoxia, in addition to further sensitizing these cells to metformin. Moreover, we have shown that full MCT1/4 inhibition slows tumour growth and extends survival in animal models. Our results indicate MCT inhibition constitutes an effective way of targeting the hypoxic niche and generates a potential therapeutic opportunity.M.Sc