title: mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy.
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.
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Kim
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Bae
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Cheol Hyeon
authors.initials: CH
authors.lastname: Kim
authors.forename: Young-Bin
authors.initials: YB
authors.lastname: Lim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms; D020125:Mutation, Missense; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D034741:RNA, Small Interfering; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077156:Gefitinib; D020123:Sirolimus