Abstract 5434: Inhibition of monocarboxylate transporter 1 as a therapeutic strategy in small cell lung cancer: target validation studies using the MCT1 inhibitor AZD3965.

Abstract

Abstract Background. Small cell lung cancer (SCLC) accounts for ∼13% of lung cancers and frequently presents as disseminated or extensive disease. SCLC is a highly proliferative disease, with a median survival of 12-20 months with therapy, and whilst SCLC is initially chemo-sensitive relapse of chemo-resistant disease is rapid and fatal, highlighting the requirement for improved therapeutic options. Monocarboxylate transporters (MCT) such as MCT1 and 4 allow the proton-linked diffusion of monocarboxylates across cellular membranes. A number of these molecules are involved in cellular metabolism including lactate which is elevated in cancer cells that rely on glycolysis for ATP production. Reliance on glycolysis is linked to a number of factors, including Myc overexpression, rapid proliferation and a hypoxic microenvironment within the tumour, all common in SCLC. Therefore we hypothesize that SCLC cells produce high levels of lactate and will be sensitive to the MCT1 inhibitor AZD3965 and that MCT4 expression will predict for AZD3965 resistance. Results. There are a wide range of responses across the panel of cell lines including sensitivity to AZD3965 under both normoxia and hypoxia, under hypoxia only and no response to AZD3965 in either environment. Cells responding to AZD3965 had a significantly increased concentration of intracellular lactate after AZD3965 treatment whilst the lactate concentration was not elevated in AZD3965-resistant cell lines. AZD3965-sensitive cells tended to express MCT1 but not MCT4, whilst AZD3965-resistant cell lines expressed relatively high levels of MCT4. Knockdown of MCT4 in the AZD3965-resistant cell line DMS79, which overexpress MCT4, led to increased retention of intracellular lactate and sensitised these cells to MCT1 inhibition. Conversely, overexpression of MCT4 in the AZD3965-sensitive cell line NCI-H1048 resulted in a decrease in intracellular lactate and increased resistance to MCT1 inhibition. Additionally we have shown that MCT1 is frequently expressed at high levels in SCLC patient tumour samples, suggesting MCT1 is a bona fide drug target for SCLC, and that MCT4 is also expressed in a subset of tumours. Conclusions. MCT1 may represent a useful therapeutic target in the treatment of SCLC patients, however there is significant variability in response emphasising the requirement of a predictive biomarker. Our preclinical data show that MCT1 and MCT4 expression could represent such biomarkers. Additionally we suggest that monitoring of lactate levels could serve as a pharmacodynamic biomarker of MCT1 inhibition. Citation Format: Radoslaw Polanski, Cassandra L. Hodgkinson, Daisuke Nonaka, Lynsey Priest, Paul D. Smith, Fiona Blackhall, Christopher J. Morrow, Caroline Dive. Inhibition of monocarboxylate transporter 1 as a therapeutic strategy in small cell lung cancer: target validation studies using the MCT1 inhibitor AZD3965. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5434. doi:10.1158/1538-7445.AM2013-5434