Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma

• Published in: Haematologica (Roma) Vol. 102; no. 7; pp. 1247 - 1257
• Main Authors: Noble, Richard A., Bell, Natalie, Blair, Helen, Sikka, Arti, Thomas, Huw, Phillips, Nicole, Nakjang, Sirintra, Miwa, Satomi, Crossland, Rachel, Rand, Vikki, Televantou, Despina, Long, Anna, Keun, Hector C., Bacon, Chris M., Bomken, Simon, Critchlow, Susan E., Wedge, Stephen R.
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.07.2017
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers; Burkitt Lymphoma - drug therapy; Burkitt Lymphoma - genetics; Burkitt Lymphoma - metabolism; Burkitt Lymphoma - pathology; Cell Death - drug effects; Cell Line, Tumor; Drug Resistance, Neoplasm; Electron Transport Complex I - antagonists & inhibitors; Energy Metabolism - drug effects; Humans; Lactic Acid - metabolism; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Mitochondria - drug effects; Mitochondria - metabolism; Monocarboxylic Acid Transporters - antagonists & inhibitors; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; Oxidative Phosphorylation - drug effects; Pyrimidinones - pharmacology; Pyrimidinones - therapeutic use; Symporters - antagonists & inhibitors; Symporters - genetics; Symporters - metabolism; Thiophenes - pharmacology; Thiophenes - therapeutic use
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2016.163030

Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed : daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death and reduced CA46 disease burden These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.