Abstract B25: The Effects of PI3K/Akt/mTOR Pathway Inhibitors on a Panel of Non Small Cell Lung Cancer (NSCLC) Cell Lines
| Autor: | Susan Heavey, Martin P. Barr, Kathy Gately, Anthony Davies, Kenneth J. O'Byrne |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Clinical Cancer Research. 18:B25-B25 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Introduction: The purpose of this study is to investigate the effects of two PI3K pathway inhibitors on a panel of NSCLC cell lines, with a view to developing resistant cell line models, through exposure to the inhibitors over an extended period of time. The PI3K/Akt/ mTOR pathway regulates cell growth and proliferation and is often dysregulated in cancer due to mutation, amplification, deletion, methylation and posttranslational modifications. Multiple novel agents, targeting different regulators within the pathway are currently under development. GDC-0941 is a PI3K targeted inhibitor which is currently in phase Ib trials for combination treatment with bevacizumab, trastuzumab and erlotinib in metastatic NSCLC. GDC-0980 is a selective dual inhibitor of PI3K and mTOR, which is currently in phase I trials for combination treatment with bevacizumab, trastuzumab, and capecitabine in solid tumors. Methods: The effects of GDC-0941 and GDC-0980 were assessed in a panel of lung cancer cells, including normal human bronchial epithelial cells (HBECs), H460 cells (PI3KCA & KRAS mutant), A549 cells (wild-type PI3KCA & KRAS mutated), cisplatin resistant H460 and A549 cells and H1975 cells (PI3KCA mutant /T790M mutant EGFR TKI resistant). The effect of each inhibitor on pAkt levels was examined by Western blot. Effects of the inhibitors on apoptosis and proliferation were analyzed by high content analysis and BrdU assays respectively. IC25 values obtained from these experiments were then used to begin treating cells over an extended period of time, in order to develop a cell line model of resistance. Results: Treatment of the panel of cell lines with either GDC-0941 or GDC-0980 resulted in reduced pAkt levels as observed by Western blot, as well as dose-dependent increased apoptosis and decreased proliferation of cell lines. IC25 values are currently being used to treat cell lines over an extended period of time in order to develop models of resistance to the two inhibitors. Discussion: Both GDC-0941 and GDC-0980 were shown to inhibit the PI3K pathway, as observed by the reduced levels of pAkt present after treatment with the inhibitors. Both inhibitors increase apoptosis and decrease proliferation in a dose-dependent manner, with GDC-0980 (dual PI3K/mTOR inhibitor) showing more significantly increased apoptosis and decreased proliferation than GDC-0941 (PI3K inhibitor). Resistant cell line models are currently being developed as a result of this research which will allow biomarkers of response/resistance to the drugs to be identified in the future. |
| Databáze: | OpenAIRE |
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