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

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 in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro 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 in vitro and reduced CA46 disease burden in vivo. 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.

[1]  F. Sotgia,et al.  Cancer metabolism: a therapeutic perspective , 2017, Nature Reviews Clinical Oncology.

[2]  A. Filby,et al.  Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia , 2016, Leukemia.

[3]  P. Goodwin,et al.  Metformin Pharmacokinetics in Mouse Tumors: Implications for Human Therapy. , 2016, Cell metabolism.

[4]  Andrea Glasauer,et al.  Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth , 2015, Cancer & metabolism.

[5]  R. Advani,et al.  Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes , 2015, Leukemia.

[6]  M. Brand,et al.  The contributions of respiration and glycolysis to extracellular acid production. , 2015, Biochimica et biophysica acta.

[7]  R. Deberardinis,et al.  MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. , 2014, Cell reports.

[8]  P. Trojer,et al.  EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. , 2014, Chemistry & biology.

[9]  B. Telfer,et al.  Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport , 2014, Molecular Cancer Therapeutics.

[10]  Mark A. Hall,et al.  Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. , 2014, Cancer research.

[11]  B. Angus,et al.  Prognostic significance of immunohistochemistry‐based markers and algorithms in immunochemotherapy‐treated diffuse large B cell lymphoma patients , 2013, Histopathology.

[12]  A. Ganser,et al.  Differential expression of miR-17∼92 identifies BCL2 as a therapeutic target in BCR-ABL-positive B-lineage acute lymphoblastic leukemia , 2013, Leukemia.

[13]  Paul D. Smith,et al.  Activity of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[14]  A. Ehrmann,et al.  BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I , 2013, Cancer medicine.

[15]  Weijun Luo,et al.  Pathview: an R/Bioconductor package for pathway-based data integration and visualization , 2013, Bioinform..

[16]  O. Heidenreich,et al.  Lentiviral marking of patient-derived acute lymphoblastic leukaemic cells allows in vivo tracking of disease progression , 2013, Leukemia.

[17]  J. Ferlay,et al.  Pediatric, elderly, and emerging adult‐onset peaks in Burkitt's lymphoma incidence diagnosed in four continents, excluding Africa , 2012, American journal of hematology.

[18]  V. Mootha,et al.  Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation , 2012, Science.

[19]  M. Dewhirst,et al.  Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis , 2012, PloS one.

[20]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[21]  A. Halestrap.  The monocarboxylate transporter family—Structure and functional characterization , 2012, IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology.

[22]  Y Lynn Wang,et al.  SYK inhibition and response prediction in diffuse large B-cell lymphoma. , 2011, Blood.

[23]  M. V. Vander Heiden,et al.  Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. , 2011, Annual review of cell and developmental biology.

[24]  J. Pouysségur,et al.  CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors , 2011, Proceedings of the National Academy of Sciences.

[25]  Jacob G. Bundy,et al.  A software complement to AMDIS for processing GC-MS metabolomic data. , 2011, Analytical biochemistry.

[26]  R. Reis,et al.  Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer , 2011, BMC Cancer.

[27]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[28]  F. Schmitt,et al.  Monocarboxylate transporter 1 is up‐regulated in basal‐like breast carcinoma , 2010, Histopathology.

[29]  O. Fiehn,et al.  FiehnLib: mass spectral and retention index libraries for metabolomics based on quadrupole and time-of-flight gas chromatography/mass spectrometry. , 2009, Analytical chemistry.

[30]  K. Kelly,et al.  Adolescent non‐Hodgkin lymphoma and Hodgkin lymphoma: state of the science , 2009, British journal of haematology.

[31]  Tiago Costa Leite,et al.  Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis. , 2007, The Biochemical journal.

[32]  Kenny Q. Ye,et al.  Transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B cell lymphomas , 2007, Proceedings of the National Academy of Sciences.

[33]  A. Barclay,et al.  CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression , 2000, The EMBO journal.

[34]  S. Stein.  An integrated method for spectrum extraction and compound identification from gas chromatography/mass spectrometry data , 1999 .

[35]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[36]  Ju-Han Lee,et al.  Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses. , 2015, Human pathology.

[37]  M. Seto,et al.  Lentiviral marking of patient-derived acute lymphoblastic leukaemic cells allows in vivo tracking of disease progression , 2013, Leukemia.

[38]  L. Staudt,et al.  Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. , 2004, Blood.