title: IL-8 confers resistance to EGFR inhibitors by inducing stem cell properties in lung cancer.
abstract: Epidermal growth factor receptor (EGFR)-targeted strategy is limited by resistance. We identify the potential genes involved in EGFR TKI (tyrosine kinase inhibitor) resistance and study the therapeutic mechanism in the non-small cell lung cancers. Potential genes involved in resistance were examined by analyzing datasets from a pair of EGFR TKI-sensitive (PC9) and TKI-resistant cells (PC9/gef). Blood specimens from patients taking EGFR TKI as first-line treatment were used to examine the correlation between drug's efficacy and IL-8 level. The effects of IL-8 on gefitinib-induced apoptosis, stemness, and in vivo tumorigenicity were investigated using established cell lines. We identified IL-8 was up-regulated in gefitinib-resistant cells, and high plasma IL-8 level was correlated with shorter progression-free-survival time. IL-8 overexpression suppressed gefitinib-induced apoptosis in gefitinib-sensitive cells. By contrast, suppression of IL-8 enhanced gefitinib-induced cell death in gefitinib-resistant cells. IL-8 also increased stem-like characteristics including aldehyde dehydrogenase activity, expression of stemness-related genes, clonogenic activity, side-population, and in vivo tumorigenicity. Consistently, knockdown of IL-8 leads to loss of stem cell-like characteristics in gefitinib-resistant cells. Our study demonstrates an important role for IL-8, and suggests IL-8 is a potential therapeutic target for overcoming EGFR TKI resistance.
authors: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yi-Nan
authors: YN
authors: Liu
authors: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Tzu-Hua
authors: TH
authors: Chang
authors: Department of Molecular Biotechnology, Dayeh University, Changhua, Taiwan.
authors: Meng-Feng
authors: MF
authors: Tsai
authors: Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan.
authors: Shang-Gin
authors: SG
authors: Wu
authors: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Tzu-Hsiu
authors: TH
authors: Tsai
authors: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors: Hsuan-Yu
authors: HY
authors: Chen
authors: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors: Sung-Liang
authors: SL
authors: Yu
authors: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Oncology, Cancer Research Center, National Taiwan University, Taipei, Taiwan.
authors: James Chih-Hsin
authors: JC
authors: Yang
authors: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors: Jin-Yuan
authors: JY
authors: Shih
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D064593:Heterografts; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; IL-8; gefitinib; resistance; stemness