Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin

Kunio Okamoto, Isamu Okamoto, Erina Hatashita, Kiyoko Kuwata, Haruka Yamaguchi, Aya Kita, Kentaro Yamanaka, Mayumi Ono, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)204-213
Number of pages10
JournalMolecular Cancer Therapeutics
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mutation
Protein-Tyrosine Kinases
Apoptosis
Erlotinib Hydrochloride
Down-Regulation
Nude Mice
Protein Kinases
Small Interfering RNA
Transfection

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin. / Okamoto, Kunio; Okamoto, Isamu; Hatashita, Erina; Kuwata, Kiyoko; Yamaguchi, Haruka; Kita, Aya; Yamanaka, Kentaro; Ono, Mayumi; Nakagawa, Kazuhiko.

In: Molecular Cancer Therapeutics, Vol. 11, No. 1, 01.01.2012, p. 204-213.

Research output: Contribution to journalArticle

Okamoto, K, Okamoto, I, Hatashita, E, Kuwata, K, Yamaguchi, H, Kita, A, Yamanaka, K, Ono, M & Nakagawa, K 2012, 'Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin', Molecular Cancer Therapeutics, vol. 11, no. 1, pp. 204-213. https://doi.org/10.1158/1535-7163.MCT-11-0638
Okamoto, Kunio ; Okamoto, Isamu ; Hatashita, Erina ; Kuwata, Kiyoko ; Yamaguchi, Haruka ; Kita, Aya ; Yamanaka, Kentaro ; Ono, Mayumi ; Nakagawa, Kazuhiko. / Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 1. pp. 204-213.
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