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.
Highlights
Lung cancer is the leading cause of cancerrelated deaths worldwide [1]
We examined expression of IL-1A, IL-1B, IL-6 and IL-8 in two pairs of gefitinibsensitive (PC9, and HCC827) and gefitinib-resistant (PC9/ gef, and HCC827/gef) lung cancer cell lines to identify the specific cytokine involved in gefitinib resistance by Real-time quantitative reverse transcriptionPCR (RT-qPCR)
We showed that IL-1A, IL-6, and IL-8 were up-regulated in PC9/gef, but only IL-8 Messenger RNA (mRNA) was up-regulated in HCC827/gef (Fig. 1a-b)
Summary
Lung cancer is the leading cause of cancerrelated deaths worldwide [1]. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are successfully used in non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations [2]. Despite early responses to EGFR-TKIs, cancers develop resistance after around 10 months of therapy. The EGFRT790M secondary mutation and c-MET amplification contribute to the majority of acquired resistance [3]. There are still some resistant mechanisms are incompletely understood. To facilitate the development of effective therapies against NSCLC, we elucidate the EGFR TKI-resistance machinery underlying tumor progression
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