Abstract 774: EGFR-regulated RGS expression contributes to paclitaxel resistance in human lung cancer cells

Abstract

Abstract Lung cancer is one of the main causes of cancer-related death worldwide, and the 5-year survival of lung cancer is less than 20%. Paclitaxel is a widely used chemotherapeutic agent to treat a variety of cancers, but its therapeutic efficacy tends to be limited due to the development of drug resistance, raising the need to understand the molecular mechanisms underlying paclitaxel resistance. In the current study, we investigated the mechanisms of paclitaxel resistance in non-small cell lung cancers (NSCLCs). First, we established paclitaxel-resistant NSCLC cell lines, including H460 TxR and SK-MES TxR, by pulse- or prolonged treatment of paclitaxel. The IC50 value of paclitaxel-resistant cell lines was 50 fold less than that of parental cells. Upon paclitaxel treatment, H460 TxR and SK-MES TxR sublines experienced markedly greater anchorage-dependent and -independent colony forming abilities with reduced apoptosis than did the parental cell lines. Next, we investigated the underlying molecular mechanism of acquired resistance against paclitaxel. Through microarray analysis, we found 19 genes commonly-increased both in H460 TxR and SK-MES TxR. Among them, the expression of regulator of G-protein signaling (RGS) gene increased the most. Knockdown of RGS gene expression by siRNA sensitized the paclitaxel-resistant cells to the drug treatment in vitro. Furthermore, H460 TxR xenograft mice showed a significant decrease in tumor growth after combined treatment with siRGS and paclitaxel, implying the association of RGS with paclitaxel resistance in NSCLC. To identify the mechanisms involved in increase in RGS expression, we assessed the phosphorylation level of several kinases involved in cell proliferation and survival. Among them, epidermal growth factor receptor (EGFR) showed the most significant phosphorylation. EGFR inhibition by erlotinib down-regulated RGS expression in a transcriptional level, leading to the enhanced sensitivity to paclitaxel in H460 TxR. Taken together, our results indicate that RGS overexpression is a mediator of paclitaxel resistance in NSCLCs and represent the first link between RGS and chemoresistance. We suggest that RGS might be a potential target of therapeutic strategies for lung cancer patients with paclitaxel resistance. Citation Format: Shin-Hyung Park, Myung-A Sung, Ho-Young Lee. EGFR-regulated RGS expression contributes to paclitaxel resistance in human lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 774. doi:10.1158/1538-7445.AM2014-774