Abstract #2788

Monocarboxylate transporter 1 (MCT1) inhibition with AZD3965 leads to MRS-detectable MCT4-dependent blockade of lactate efflux and pyruvate-lactate exchange in human cancer cells providing potential for non-invasive imaging

Mounia Beloueche-Babari¹, Slawomir Wantuch¹, Harold G Parkes¹, Markella Koniordou¹, Vaitha Arunan¹, Thomas R Eykyn¹, Paul D Smith², and Martin O Leach¹

¹CRUK Cancer Imaging Centre, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, United Kingdom, ²AstraZeneca, Cambridge, United Kingdom

The monocarboxylate transporter 1 (MCT1), which mediates the bidirectional movement of molecules such as lactate and pyruvate, is upregulated in cancer and constitutes a promising drug target. Using MRS we investigate the impact of the MCT1 inhibitor AZD3965, currently in phase-I clinical trials, on human cancer cell metabolism to assess potential for pharmacodynamic biomarker discovery. We show that AZD3965 inhibits lactate efflux and blocks hyperpolarised ¹³C-pyruvate-lactate exchange in human cancer cells in an MCT4-dependent manner. Thus, intracellular lactate and hyperpolarized ¹³C-pyruvate-lactate exchange are promising metabolic imaging biomarkers for monitoring the action of AZD3965 and potentially other MCT1 inhibitors.

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