Inhibition of monocarboxylate transporter 1 by AZD3965 as a therapeutic approach in oncology

Abstract

Many tumours display a metabolic phenotype distinct from non‐malignant cells, with an increased reliance on glycolysis. This results in a greater production of lactate even under aerobic conditions. Lactate efflux is facilitated by monocarboxylate transporters 1‐4 (MCT1‐4) and is essential to maintain energy homeostasis. A sub‐group of cancers express only MCT1 and are therefore exclusively reliant on this transporter to export lactate. Inhibition of MCT1 has been proposed as a therapeutic approach to prevent lactate export in tumour cells with low MCT4. In this thesis, inhibition of monocarboxylate transporter 1 (MCT1) was investigated using the oral MCT1 inhibitor AZD3965 which is currently undergoing phase I clinical development. Low MCT4 expression was found to be a common characteristic of Burkitt lymphoma (BL) and Diffuse Large B‐cell Lymphoma (DLBCL) in immortalised cell lines and patient samples. In cell line models AZD3956 treatment caused a rapid accumulation of intracellular lactate and altered cellular metabolite profiles consistent with feedback inhibition of glycolysis including an increase in TCA cycle intermediates. A substantial growth inhibitory response was observed in vitro in BL and DLBCL cell lines and also in an in vivo model of BL following daily oral AZD3965 treatment. The combination with a mitochondrial Complex I inhibitor, BAY 87‐2243, triggered significant lymphoma cell death in vitro and also reduced disease burden in vivo. This work supports the use of AZD3965 in the treatment of lymphoma patients who have become refractory to standard therapy but also highlights the potential need for combination strategies to optimally target the altered tumour metabolic phenotype.