title: A pilot study for the early assessment of the effects of BMS-754807 plus gefitinib in an H292 tumor model by [(18)F]fluorothymidine-positron emission tomography.
abstract: BMS-754807 is an inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor that also represses aurora kinase. Cancers that express high levels of IGF-1/IGF-1R are sensitive to BMS-754807; however, it shows limited efficacy in non-small cell lung cancer (NSCLC) in which IGF-1R-driven signals may not be dominant factors in cell proliferation. In this study, we investigated whether a combination of BMS-754807 and gefitinib would be synergistic in H292 NSCLC and whether [(18)F]fluorothymidine ([(18)F]FLT)-positron emission tomography (PET) could predict the effects. We found that BMS-754807 synergized with gefitinib in reducing cell viability (combination index=0.38) and Akt phosphorylation, and increasing the subG1 fraction in H292 cells. BMS-754807 alone and in combination with gefitinib increased the cells in G2M phase and polyploid cells and decreased the phosphorylation of IGF-1R and histone H3. The inhibition of tumor growth by gefitinib was increased by BMS-754807 (%T/C, 17.5 % vs. 58.0 % for gefitinib alone and combined treatment, respectively), although BMS-754807 alone had little effect. The standardized uptake value by [(18)F]FLT-PET were increased in vehicle-treated mice by 73 %, minimally changed in gefitinib- or BMS-754807-treated mice, whereas decreased in co-treated mice by -48.8 % between day 0 and day 3. The combination therapy with BMS-754807 and gefitinib might be a more effective anticancer strategy than BMS-754807 alone in tumors that are less IGF-1R-dependent and that [(18)F]FLT-PET can be used to assess early therapeutic responses.
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Haeng Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seog Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Oh
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Ryu
authors.forename: Dae Hyuk
authors.initials: DH
authors.lastname: Moon
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005462:Fluorine Radioisotopes; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives; D014227:Triazines / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C545990:BMS 754807; D005462:Fluorine Radioisotopes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D014227:Triazines; D017526:Receptor, IGF Type 1; D000077156:Gefitinib; D013936:Thymidine