Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer

Abstract

ABSTRACT Increased glycolytic rates in cancer cells generate high levels of lactate that are exported by the monocarboxylate transporters (MCTs) 1-4. AZD3965 is an orally bioavailable inhibitor of MCT-1 that was originally developed by AstraZeneca (Macclesfield, England, UK) for use in transplant rejection / autoimmune disease. It has increased selectivity for MCT1 over MCT2 and does not inhibit MCT4. A Cancer Research UK phase I study of AZD3965 in solid tumours is ongoing (NCT01791595). Small cell lung cancer (SCLC) is a highly proliferative tumour proposed to be reliant on glycolysis. We therefore conducted preclinical evaluation of AZD3965 in SCLC cell lines and xenografts with the aims to determine its therapeutic potential and putative predictive biomarkers for application in clinical trials. A cohort of tumour biopsies from SCLC patient s was also assessed for expression and clinical significance of MCT1, MCT4 and the hypoxia marker, CAIX. In seven SCLC cell lines sensitivity to AZD3965 varied and was highest in hypoxic culture conditions. Resistance was associated with high expression of MCT4. Treatment of the COR-L103 SCLC xenograft model with AZD3965 resulted in growth inhibition and increased levels of intratumour lactate. A tissue microarray (TMA) was constructed for 78 patients, immunostained with anti-MCT1, MCT4 and CAIX antibodies and scored by two independent observers. Clinical outcome data was available for 47 patients. Patients were stratified into MCT1 high/low, MCT4 high/low or CAIX high/low based on the median immunoscore from the complete TMA dataset. There were no significant associations with known clinical prognostic factors such as lactate dehydrogenase. Higher MCT1 expression was significantly associated with worse survival in univariate analysis (p = 0.014). A pattern of high MCT1 and hypoxia marker CAIX expression with low MCT4 expression was observed in 21% of SCLC cases. The preclinical results provide a rationale to evaluate AZD3965 in patients with SCLC, in particular those with presence of hypoxia, high MCT1 and low MCT4 expression. (Polanski et al. 2013 Clin Cancer Res; 20(4) 926-937)