Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: Limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways

摘要: The epidermal growth factor receptor (EGFR) is an important novel target for anticancer therapy. In this study, we examined the molecular mechanisms that underlie antitumor effects of anti-EGFR monoclonal antibody C225 (Cetuximab) and selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca) in non-small cell lung cancer (NSCLC) lines. Cell growth, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was inhibited at low concentrations control A431 cells, whereas NSCLC lines were comparatively more resistant. but not treatment resulted a modest increase DNA fragmentation, externalization phosphatidyl serine, activation caspase-3, known markers apoptotic death. However, poly(ADP-ribose) polymerase cleavage detected, caspase inhibition carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone partially reduced ZD1839-generated fragmentation. Overexpression antiapoptotic protein Bcl-2 cells suppressed cytotoxicity upon treatment. These results thus demonstrate toxic effect caused form death involves mitochondrial step is, least part, dependent on activation. expression levels showed no significant correlation with sensitivity to C225. Evaluation mitogen-activated kinase/extracellular signal-regulated phosphatidylinositol 3'-kinase/Akt pathways considerable these one or both remained active cells. addition, specific inhibitors 3'-kinase smaller proliferation than simultaneous inhibitors, induction apoptosis observed only when blocked. Together, data suggest persistent activity either signaling involved lack inhibitors.