A pilot study for the early assessment of the effects of BMS-754807 plus gefitinib in an H292 tumor model by [18F]fluorothymidine-positron emission tomography
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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 [18F]fluorothymidine ([18F]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 [18F]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 [18F]FLT-PET can be used to assess early therapeutic responses.
KeywordsBMS-754807 Epidermal growth factor receptor [18F]fluorothymidine Gefitinib Insulin-like growth factor-1 receptor Non-small cell lung cancer Positron emission tomography
This study was supported by a grant from the Asan Institute for Life Science (No. 2009–430) and Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education, Science and Technology(2010-0025392). We thank for Bristol-Myers Squibb and AstraZeneca for the kind provision of BMS-754807 and gefitinib, respectively.
Conflict of interest
The authors declare that they have no conflict of interest.
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