Overcoming Erlotinib Resistance in EGFR Mutation–Positive Non–Small Cell Lung Cancer Cells by Targeting Survivin

Molecular Cancer Therapeutics - Tập 11 Số 1 - Trang 204-213 - 2012
Kunio Okamoto1, Isamu Okamoto1, Erina Hatashita1, Kiyoko Kuwata1, Haruka Yamaguchi1, Aya Kita1, Kentaro Yamanaka1, Mayumi Ono1, Kazuhiko Nakagawa1
1Authors' Affiliations: 1Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka; 2Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki; and 3Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

Tóm tắt

Abstract Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation–positive non–small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR–TKIs contributes to EGFR–TKI-induced apoptosis in EGFR mutation–positive NSCLC cells. We have now investigated the role of survivin expression in EGFR–TKI resistance induced by PTEN loss. The EGFR–TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation–positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation–positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT–survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation–positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR–TKI resistance in EGFR mutation–positive NSCLC. Mol Cancer Ther; 11(1); 204–13. ©2011 AACR.

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Molecular Cancer Therapeutics

Tập 11 Số 1

204-213

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