Abstract

Glucose Deprivation Drives Adaptation Towards Lactate Utilisation and Sensitises Tumour Cells to the First-in-class Monocarboxylate Transporter 1 (MCT1) Inhibitor AZD3965

Shyam Solanki, Student, Imperial College London

Due to an abnormal vasculature and intratumoural ‘glucose sinks’, regions within solid tumours may be chronically or acutely glucose deprived. In these regions lactate utilisation via MCT1 may be crucial to tumour cell metabolism, fuelling energy production and allowing cell survival or growth. By altering the nutrient composition of the tumour cell microenvironment and combining molecular and stable-isotope analyses (NMR, GCMS), we looked to determine the influence of glucose availability on lactate utilisation. When deprived of glucose, lactate became a major source of intracellular pyruvate and TCA metabolites in several tumour cell lines and maintained ATP levels. Moreover, lactate became a key contributor to fatty-acid synthesis, suggesting it can support tumour cell growth and proliferation through lipid anabolism. Lactate supplementation under glucose deprivation upregulated MCT1, LDHB and downregulated LDHA expression, suggesting adaptive tumour cell response towards lactate utilisation. Under these conditions, MCT1 inhibition by the clinical candidate AZD3965 attenuated lactate uptake, and utilisation- and triggered growth inhibition. Our findings suggest lactate utilisation via MCT1 could be an important phenomenon in some tumours, contributing to cell catabolism, anabolism, and survival, growth and proliferation by remodelling tumour cell metabolism in hyperlactaemic and glucose deprived microenvironments. Based on our observations we propose rational drug combination of MCT1 inhibitors with compounds that target glucose metabolism may be a viable and effective strategy in anti-cancer therapy.