title: Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer.
abstract: OBJECTIVE
  The monocarboxylate transporter 1 (MCT1) inhibitor, AZD3965, is undergoing phase I evaluation in the United Kingdom. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use.
  
  
  METHODS
  AZD3965 sensitivity was determined for seven SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 was assessed by Western blot analysis. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray (TMA) from 78 patients with SCLC.
  
  
  RESULTS
  AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intratumor lactate. In the TMA, high MCT1 expression was associated with worse prognosis (P = 0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors.
  
  
  CONCLUSIONS
  This study provides a rationale to test AZD3965 in patients with SCLC. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond.
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Radosław
authors.initials: R
authors.lastname: Polański
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.affiliation: Christie National Health Service Foundation Trust, Manchester, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fusi
authors.affiliation: Christie National Health Service Foundation Trust, Manchester, UK.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nonaka
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.|Christie National Health Service Foundation Trust, Manchester, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Priest
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Kelly
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Trapani
authors.affiliation: University Hospital of South Manchester National Health Service Foundation Trust, Manchester, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Bishop
authors.affiliation: Faculty of Life Sciences, Manchester Academic Health Sciences Centre, University of Manchester, UK.|Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: White
authors.affiliation: Oncology iMED, AstraZeneca, Macclesfield, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.affiliation: Oncology iMED, AstraZeneca, Macclesfield, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.|Christie National Health Service Foundation Trust, Manchester, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015999:Multivariate Analysis; D009124:Muscle Proteins / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000970:Antineoplastic Agents; 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