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

Eun Ju Kim, Jae Hoon Jeong, Sangwoo Bae, Seongman Kang, Cheol Hyeon Kim, Young Bin Lim

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1248-1256
Number of pages9
JournalJournal of cellular biochemistry
Volume114
Issue number6
DOIs
Publication statusPublished - 2013 Jun

Keywords

  • NSCLC
  • PTEN
  • Radiosensitivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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