P3.02b-123 Lysimachia Capillipes Capilliposide Inhibits AKT Activation and Restores Sensitivity to Gefitinib in NSCLC with Acquired Gefitinib Resistance: Topic: EGFR RES

Abstract

Most non-small cell lung cancer (NSCLC) patients responding to gefitinib will eventually develop the resistance. Lysimachia capillipes (LC) capilliposide extracts from LC hemsl shows both in vitro and in vivo anti-cancer effects. We investigated whether LC capilliposide combined with gefitinib could overcome the resistance of NSCLC cells to gefitinib, and to identify the involved molecular signaling. NSCLC cell lines with different sensitivities to gefitinib were studied. Cell proliferation was assessed with MTT assay. Cell apoptosis and cell cycle distribution were measured using cytometry. EGFR-related signaling proteins and Human Phospho-Kinase were analyzed using Western blotting and protein array, respectively. Tumor growth inhibition were evaluated in PC-9-GR xenograft. CC3, Ki67 and pEGFR were assessed by IHC on tumor tissues. LC capilliposide inhibited cell growth in gefitinib-sensitive and -resistant cells. In gefitinib resistant cell PC-9-GR with T790M mutation, the LC capilliposide combined with gefitinib was potent in cell growth inhibition and apoptosis induction, but no obvious effect on gefitinib-induced G0/G1 arrest. LC capilliposide remarkable blocks the phosphorylation of EGFR downstream signaling molecule AKT, on which LC capilliposide and gefitinib alone had no obvious effect. The Human Phospho-Kinase array further confirmed the enhanced inhibitory effect on the AKT signaling. LC capilliposide treatment also enhanced tumor growth inhibition when combined with gefitinib in PC-9-GR xenografts. LC capilliposide restored the sensitivity to gefitinib in NSCLC cells with acquired gefitinib resistance, suggesting that combination of LC and gefitinib may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLCs with T790M mutation.