Anti-tumor activity and acquired resistance mechanism of dovitinib (TKI258) in RET rearranged lung adenocarcinoma

Abstract

RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, on RET-rearranged LADC has not been known. The aims of the study are to explore antitumor effects and mechanism of acquired resistance of dovitinib in RET-rearranged LADC. In silico analysis results indicated that dovitinib strongly interacts with the surrounding residues in RET kinase domain, dovitinib potently induced cell cycle arrest in G1 phase and does-dependent suppression of phosphorylation of RET and ERK in LC-2/ad LADC cells harboring CCDC6-RET rearrangement. The therapeutic effects of dovitinib were photocopied by siRNA knockdown of RET. Selective inhibition of dovitinib on autophosphorylation of RET kinases was confirmed in HEK293 cells expressing KIF5B-RET or CCDC6-RET. A phospho-RTK array reveals that LC-2/ad cells maintain phosphorylation of FGFRs and VEGFRs in the presence of dovitinib. Dovitinib inhibited ERK phosphorylation more efficiently than vandetanib, sunitinib and sorafenib. The effects on ERK phosphorylation were correlated with the results of cell viability assays. Antitumor effect of dovitinib was observed in tumor xenograft model. To identify the acquired resistance mechanism, dovitinib-resistant cells (LC-2/ad DR) were established by exposure of LC-2/ad to stepwise increasing concentration of dovitinib. Knockdown of RET or dovitinib treatment did not inhibit ERK phosphorylation in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK phosphorylation and growth of LC-2/ad DR cells. Taken together, dovitinib can be a potential therapeutic option for RET-rearranged LADC, and acquired resistance to dovitinib can be overcome by targeting SRC.