In vitro sequence-dependent interaction between paclitaxel and gefitinib in human lung cancer cell lines

e22025 Background: Cytotoxicity chemotherapy has been standard first line treatment for advanced NSCLC. Clinical trials comparing first line EGFR TKI therapy over cytotoxicity chemotherapy are under investigation in phase III trials. The aim of this study is to test the hypothesis that paclitaxel followed by gefitinib would be superior to the opposite order in EGFR TKI resistant cell lines because of cell signaling pathway and cell cycle interaction. Methods: we have used EGFR-TKI resistant human lung cancer cell lines A549, H1975 and H1650 as an in vitro model for defining the differential effects of opposite sequence of combination of cytotoxic drug and anti- EGFR agents on cell growth, signaling pathway, cell cycle distribution and induction of apoptosis. Results: Paclitaxel 24 hours followed by gefitinib 72 hours in A549, H1975 and H1650 cells produced synergistic effects, while the reverse sequence produced antagonistic effects. Exposure to paclitaxel resulted in an increased pEGFR and pAKT level, this increase of phosphorylation can be inhibited by the following gefitinib exposure, while the reverse sequence resulted in no change in EGFR and AKT phosphorylation. We confirmed that gefitinib arrested the cells in G1, paclitaxel arrested cells in S phase. The sequence of paclitaxel followed by gefitinib cause cells arrested in G1, while the reverse sequence cause cells arrested in S and G2 phase. Conclusions: These findings suggest that the sequence of paclitaxel followed by gefitinib may be superior to the reverse sequence in gefitinib resistant NSCLC, and support the investigation of these sequential treatment in the clinical setting. This work was supported by the grants from the National Natural Science Foundation of China (No. 30772531). No significant financial relationships to disclose.