Abstract
Abstract Background: RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib, a potent inhibitor of FGFR, VEGFR, and PDGFR, on RET-rearranged LADC is not known. This aims of the study are to explore anti-tumor effects and mechanism of acquired resistance of dovitinib in RET-rearranged LADC. Results: Dovitinib potently induced cell cycle arrest in G1 phase and dose-dependent suppression of phosphorylation of RET and ERK in LC-2/ad LADC cells harboring CCDC6-RET rearrangement. Selective inhibition of dovitinib on autophosphorylation of RET kinases was confirmed in HEK293 cells expressing KIF5B-RET or CCDC6-RET. In Human RTK array, dovitinib did not show significant inhibition of phosphorylation on FGFR or VEGFR in LC-2/ad cells. Dovitinib exhibited growth inhibition of LC-2/ad cells more efficiently than vandetanib, sunitinib, and sorafenib, which was confirmed in vivo xenograft models. To identify the acquired resistance mechanism, we established resistant cells to dovitinib (LC-2/ad DR) from LC-2/ad cell line. Knockdown of RET or dovitinib did not inhibit RET-induced ERK phosphorylation in LC-2/ad DR cells. Using microarray and immunoblotting, we confirmed aberrant focal adhesion kinase signaling, including c-Src. Dasatinib, a Src inhibitor, suppressed ERK phosphorylation and growth of LC-2/ad DR cells. Conclusion: Dovitinib can be a potential therapeutic option for RET-rearranged LADC. Acquired resistance to dovitinib can be overcome by targeting SRC. Citation Format: Chan Woo Kang, Kang Won Jang, Byoung Chul Cho. Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 741. doi:10.1158/1538-7445.AM2015-741
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
