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Journal of Cellular Biochemistry

mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy

Authors

  • Eun Ju Kim,

    1. Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
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  • Jae-Hoon Jeong,

    1. Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
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  • Sangwoo Bae,

    1. Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
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  • Seongman Kang,

    1. School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea
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  • Cheol Hyeon Kim,

    Corresponding author
    1. Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
    • Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
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  • Young-Bin Lim

    Corresponding author
    1. Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
    • Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
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  • The authors have no conflict of interest.

  • Young-Bin Lim and Cheol Hyeon Kim contributed equally to this work.

Abstract

Clinical resistance to gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in patients with lung cancer has been linked to acquisition of the T790M resistance mutation in activated EGFR or amplification of MET. Phosphatase and tensin homolog (PTEN) loss has been recently reported as a gefitinib resistance mechanism in lung cancer. The aim of this study was to evaluate the efficacy of radiotherapy in non-small-cell lung cancer (NSCLC) with acquired gefitinib resistance caused by PTEN deficiency to suggest radiotherapy as an alternative to EGFR TKIs. PTEN deficient-mediated gefitinib resistance was generated in HCC827 cells, an EGFR TKI sensitive NSCLC cell line, by PTEN knockdown with a lentiviral vector expressing short hairpin RNA-targeting PTEN. The impact of PTEN knockdown on sensitivity to radiation in the presence or absence of PTEN downstream signaling inhibitors was investigated. PTEN knockdown conferred acquired resistance not only to gefitinib but also to radiation on HCC827 cells. mTOR inhibitors alone failed to reduce HCC827 cell viability, regardless of PTEN expression, but ameliorated PTEN knockdown-induced radioresistance. PTEN knockdown-mediated radioresistance was accompanied by repression of radiation-induced cytotoxic autophagy, and treatment with mTOR inhibitors released the repression of cytotoxic autophagy to overcome PTEN knockdown-induced radioresistance in HCC827 cells. These results suggest that inhibiting mTOR signaling could be an effective strategy to radiosensitize NSCLC harboring the EGFR activating mutation that acquires resistance to both TKIs and radiotherapy due to PTEN loss or inactivation mutations. J. Cell. Biochem. 114: 1248–1256, 2013. © 2012 Wiley Periodicals, Inc.

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