Abstract B46: Soluble AXL is a candidate circulating biomarker for predicting acquired and intrinsic resistance to molecular-targeted agents in NSCLC cells.

Abstract

Abstract Background: Drug resistance is an important factor that compromise therapeutic effect of most anti-cancer drugs including molecular-targeted agents. Non-invasive assessment of drug resistance by circulating biomarkers would therefore be useful for determining therapeutic options for resistant patients. Recently, a receptor tyrosine kinase AXL has been implicated in acquired resistance to EGFR inhibitors in NSCLC cells. In this study, we examined the potential utility of AXL as a circulating biomarker to predict acquired or intrinsic drug resistance using NSCLC cells. Materials and methods: Drug resistant NSCLC cell lines were developed by exposing NSCLC cells with either EGFR inhibitor gefitinib or MET inhibitor PHA-665752. AXL-positive cells in parent and established resistant cell lines were isolated by anti-AXL antibody-immobilized magnetic beads. Drug resistance was assessed by MTS growth inhibition assay. Immunoblot analysis was performed on cell lysate and conditioned medium to evaluate expression and release of AXL. The role of AXL in cell growth and motility was examined by MTS growth inhibition assay and transwell migration assay. Results: Drug-resistant NSCLC cell lines were successfully established, and increased release of fragmented soluble form of AXL was observed in these cell lines. They showed increased cell motility, which was effectively inhibited by AXL knockdown using siRNA. In contrast, their cell growth was not affected by AXL knockdown, even when these cells were simultaneously treated with molecular-targeted agents. Furthermore, cells highly expressing AXL were immunologically isolated from a gefitinib-sensitive parent cell line. These cells showed partial resistance to gefitinib, indicating that such cells intrinsically exist in NSCLC cell populations. Conclusions: Soluble form of AXL is a candidate circulating biomarker for predicting acquired and intrinsic resistance to molecular-targeted agents in NSCLC cells. It may also be used to predict AXL-mediated increased motility of resistant cells. Patients harboring such resistant cells may have increased chance of responding to AXL-targeted anti-metastasis therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B46. Citation Format: Nobuyuki Ise, Nobuaki Takemori, Kazuya Omi, Katsutoshi Goishi, Shigeki Higashiyama. Soluble AXL is a candidate circulating biomarker for predicting acquired and intrinsic resistance to molecular-targeted agents in NSCLC cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B46.