Objectives: To investigate the mechanism of gefitinib resistance in renal cell carcinoma (RCC) cells. Although epidermal growth factor receptor (EGFR) is frequently overexpressed in RCC, gefitinib, a tyrosine kinase inhibitor of EGFR, has only a limited antitumor effect on RCC. Methods: The effects of gefitinib on the activation status of EGFR and kinases downstream in its signaling cascade were examined in three gefitinib-resistant RCC cell lines: SKRC-44, KU20-01, and 786-O. The changes in signaling cascades and cell survival that were induced by gefitinib in combination with either the phosphatidylinositol 3-kinase inhibitor LY294002 or the knockdown of Akt expression by transient transfection with Akt small interfering RNA were examined in 786-O cells. Results: Gefitinib alone did not significantly reduce cell viability in any of the examined cell lines. Although in each line, the phosphorylation of EGFR and extracellular signal-regulated kinase was inhibited by 0.1 μM gefitinib, the phosphorylation of Akt was constitutive and was not inhibited by even 10 μM gefitinib. In 786-O cells, the phosphorylation of both extracellular signal-regulated kinase and Akt was inhibited by gefitinib used in combination with either LY294002 or the knockdown of Akt expression, and the viability of 786-O cells was suppressed significantly by gefitinib used in combination with LY294002 (P < .0001) or Akt small interfering RNA (P = .0044). Conclusions: Constitutively activated Akt might prevent the antitumor efficacy of gefitinib in renal cell carcinoma, and the therapeutic effectiveness of gefitinib might be improved by inhibiting Akt activation.
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