title: BMS-690514, a VEGFR and EGFR tyrosine kinase inhibitor, shows anti-tumoural activity on non-small-cell lung cancer xenografts and induces sequence-dependent synergistic effect with radiation.
abstract: BACKGROUND
  Non-small-cell lung cancer (NSCLC) is an aggressive disease in which vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are implicated in tumour growth, tumour resistance to radiation and chemotherapy, and disease relapse. We have investigated the anti-tumoural effects of BMS-690514, an inhibitor of both vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signalling pathways, as a single agent and in combination with ionising radiation (IR) on several NSCLC cell lines.
  
  
  METHODS
  Radiosensitisation of several NSCLC cell lines by BMS-690514 was assessed in vitro using clonogenic assay and in vivo using nude mice.
  
  
  RESULTS
  In vitro studies showed that BMS-690514 alone decreases clonogenic survival of NSCLC cells lines but no potential enhancement of IR response was observed in the combination. In tumour-bearing mice, BMS-690514 alone inhibits the growth of NSCLC xenografts, including the T790M mutation-harbouring H1975 tumour. The concomitant combination of BMS-690514 and radiation did not increase mice survival in comparison with treatment with IR alone. In contrast, BMS-690514 markedly enhances the anti-tumour effect of radiation in a sequential manner on H1299 and H1975 xenografts. Immunohistochemistry revealed a qualitative reduction in vessel area after administrations of BMS-690514, compared with vehicle-treated controls, suggesting that revascularisation may explain the schedule dependency of the tumour-growth delay observed.
  
  
  CONCLUSIONS
  The results of association with radiation show that BMS-690514 may be a successful adjuvant to clinical radiotherapy. These findings are of translational importance because the clinical benefits of anti-EGFR and anti-VEGFR therapy might be schedule dependent.
authors.affiliation: Institut Gustave Roussy, UPRES 27-10, 39 rue Camille Desmoulins, 94800 Villejuif, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Loriot
authors.forename: P
authors.initials: P
authors.lastname: Mordant
authors.forename: N
authors.initials: N
authors.lastname: Dorvault
authors.forename: T
authors.initials: T
authors.lastname: De la motte Rouge
authors.forename: J
authors.initials: J
authors.lastname: Bourhis
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
authors.forename: E
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005091:Exons; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D017384:Sequence Deletion; D014183:Transplantation, Heterologous; D014227:Triazines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C552150:BMS-690514; D010880:Piperidines; D011758:Pyrroles; D014227:Triazines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor