Effects of Src Inhibitors on Cell Growth and Epidermal Growth Factor Receptor and MET Signaling in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells With Acquired MET Amplification

摘要: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as gefitinib and erlotinib in non-small cell lung cancer (NSCLC) is often limited by the emergence drug resistance conferred either a secondary T790M mutation EGFR or acquired amplification MET gene. We now show that extent activation tyrosine Src markedly increased gefitinib-resistant NSCLC (HCC827 GR) cells with compared gefitinib-sensitive parental (HCC827) cells. In contrast, did not differ between (PC9/ZD) harboring corresponding (PC9) This HCC827 GR was largely abolished MET-TKI PHA-665752 but only partially inhibited gefitinib, suggesting more dependent on signaling than amplification. blocked Akt Erk pathways, resulting both suppression induction apoptosis, effectively combination PHA-665752. Furthermore, inhibitor dasatinib tumor xenografts to significantly greater treatment alone. These results provide rationale for clinical targeting