title: ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors.
abstract: Molecular targeting therapeutics, such as EGFR tyrosine kinase inhibitors (TKIs), are important treatment strategies for lung cancer. Currently, the major challenge confronting targeted cancer therapies is the development of resistance. Cancer stem cells (CSCs) represent a rare population of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance and spreading. Resistance to conventional chemotherapeutic drugs is a common characteristic of CSCs. However, the issue of whether CSCs contribute to EGFR TKI resistance in lung cancer is yet to be established. In the current study, we explored the association of ALDH1A1 expression with EGFR TKI resistance in lung cancer stem cells. ALDH1A1-positive lung cancer cells displayed resistance to gefitinib, compared to ALDH1A1-negative lung cancer cells. Moreover, PC9/gef cells (gefitinib-resistant lung cancer cells) presented a higher proportion of ALDH1A1-positive cells, compared to PC9 cells (gefitinib-sensitive lung cancer cells). Clinical sample studies were consistent with results from cell culture model systems showing that lung cancer cells with resistance to EGFR TKI and chemotherapy drugs contain significantly increased proportions of ALDH1A1-positive cells. These findings collectively suggest that ALDH1A1 positivity in cancer stem cells confers resistance to EGFR TKI in lung cancer.
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Po
authors.initials: CP
authors.lastname: Huang
authors.forename: Meng-Feng
authors.initials: MF
authors.lastname: Tsai
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Chang
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Tang
authors.forename: Su-Yu
authors.initials: SY
authors.lastname: Chen
authors.forename: Hsiao-Hsuan
authors.initials: HH
authors.lastname: Lai
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Shih
authors.forename: Shwu-Bin
authors.initials: SB
authors.lastname: Lin
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000444:Aldehyde Dehydrogenase; D066246:ErbB Receptors