IL-8 confers resistance to EGFR inhibitors by inducing stem cell properties in lung cancer

// Yi-Nan Liu 1 , Tzu-Hua Chang 1 , Meng-Feng Tsai 2 , Shang-Gin Wu 3 , Tzu-Hsiu Tsai 1 , Hsuan-Yu Chen 4 , Sung-Liang Yu 5 , James Chih-Hsin Yang 6, 7 , Jin-Yuan Shih 1, 8 1 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan 2 Department of Molecular Biotechnology, Dayeh University, Changhua, Taiwan 3 Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan 4 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan 6 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan 7 Graduate Institute of Oncology, Cancer Research Center, National Taiwan University, Taipei, Taiwan 8 Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan Correspondence to: Jin-Yuan Shih, e-mail: jyshih@ntu.edu.tw Keywords: IL-8, EGFR, gefitinib, resistance, stemness Received: October 15, 2014      Accepted: February 15, 2015      Published: March 18, 2015 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.