title: Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.
abstract: 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 observedin vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeksin vitroresulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell deathin vitroand reduced CA46 disease burdenin vivoThese 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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Noble
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Natalie
authors.initials: N
authors.lastname: Bell
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Helen
authors.initials: H
authors.lastname: Blair
authors.affiliation: Division of Cancer, Imperial College London.
authors.forename: Arti
authors.initials: A
authors.lastname: Sikka
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Huw
authors.initials: H
authors.lastname: Thomas
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Nicole
authors.initials: N
authors.lastname: Phillips
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Sirintra
authors.initials: S
authors.lastname: Nakjang
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne.
authors.forename: Satomi
authors.initials: S
authors.lastname: Miwa
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Rachel
authors.initials: R
authors.lastname: Crossland
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.affiliation: Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust.
authors.forename: Despina
authors.initials: D
authors.lastname: Televantou
authors.affiliation: Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust.|MRC/EPSRC Newcastle Molecular Pathology Node, Newcastle upon Tyne.
authors.forename: Anna
authors.initials: A
authors.lastname: Long
authors.affiliation: Division of Cancer, Imperial College London.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.|Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust.|MRC/EPSRC Newcastle Molecular Pathology Node, Newcastle upon Tyne.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bacon
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.|Department of Pediatric and Adolescent Hematology and Oncology, Newcastle upon Tyne Hospitals NHS Foundation Trust.
authors.forename: Simon
authors.initials: S
authors.lastname: Bomken
authors.affiliation: AstraZeneca, Cambridge, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne steve.wedge@ncl.ac.uk.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D042967:Electron Transport Complex I; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D011744:Pyrimidinones; D027981:Symporters; D013876:Thiophenes; D000099233:Monocarboxylate Transport Protein 1; C000592351:AZD3965; C406962:SLC16A4 protein, human