Activated Akt Prevents Antitumor Activity of Gefitinib in Renal Cancer Cells

Kenji Kuroda, Akio Horiguchi, Makoto Sumitomo, Takako Asano, Keiichi Ito, Masamichi Hayakawa, Tomohiko Asano

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)209-215
Number of pages7
JournalUrology
Volume74
Issue number1
DOIs
Publication statusPublished - 01-07-2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Urology

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