Abstract
Abstract Acquired tumor resistance to molecular targeted anti-cancer therapeutics poses a significant challenge in cancer therapy. Extensive studies have revealed diverse mechanisms that give rise to resistant phenotypes. The present study aims to identify phenotypic characteristics associated with acquired tumor resistance to sorafenib, a multi-targeted tyrosine kinase inhibitor, using both in vitro and in vivo sorafenib-resistant human lung cancer models. We established our in vitro sorafenib-resistant model using A549 human lung adenocarcinoma cells, which were continuously exposed to increasing concentrations of sorafenib (from 4 μM to 9 μM) over 10 months. Sorafenib-resistant A549 (A549R) cells gained the spindle-shaped morphology and exhibited an approximately 2-fold increase in the IC50 as compared with parental A549 cells [mean IC50 of 9.0 μM vs. 4.4 μM, p < 0.01 (N=6)]. Both Western blotting and immunocytochemical analysis revealed the loss of E-cadherin expression in A549R cells. Measurements of transendothelial electrical resistance (TEER; ohms) were conducted using Electric Cell Impendence Sensing (ECIS) in human umbilical vascular endothelial cell (HUVEC) monolayer co-cultured with A549 parental or A549R cells. A549R cells reduced HUVEC resistance and exhibited greater ability to invade HUVEC monolayer as compared with A549 parental cells. Our in vivo sorafenib-resistant tumor model was established by exposing A549 xenografts to once daily treatment with 40 mg/kg of sorafenib for 3 months. Complete tumor regression was observed in 5 out of 8 sorafenib-treated mice bearing A549 xenografts, while invasive tumor growth was seen in the other 3 animals. The resultant in vivo sorafenib-resistant A549 xenografts further provide evidence that the development of sorafenib resistance in A549 cells are associated with enhanced invasive and disseminative capabilities. The ongoing effort is focused on the characterization of in vivo sorafenib-resistant A549 xenografts in order to identify the important drivers of invasion and motility of human lung cancer cells with acquired resistance to sorafenib. Citation Format: Qingyu S. Zhou, Diane Allen-Gipson. Acquired sorafenib resistance is associated with enhanced invasive capability in A549 cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 970. doi:10.1158/1538-7445.AM2013-970
Published Version
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