Antitumor 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, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G 0 -G 1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

“…This finding reinforced the lack of requirement for RET signaling and suggested that chronic RET inhibition can suppress phosphorylation independent of ponatinib's ability to bind to the RET kinase domain, perhaps through increased expression of phosphatases or increased turnover of phosphorylated RET. We are not the first to report this phenomenon: dovitinib-resistant LC-2/ad cells with Src activation were also reported to have lost phosphorylation of the RET fusion protein (43). We identified several tyrosine phosphatases that were upregulated in both the PR1 and PR2 cell lines compared to the LC-2/ad control cells: PTPRG, PTPN21, PTPN14, PTPN9, and CDC14A (Table S3).…”

Losses of cytokines and chemokines are common genetic features of human cancers: the somatic copy number alterations are correlated with patient prognoses and therapeutic resistance

“…Notably, upregulation of 16 coCytokines in lapatinib-treated BT474-J4 vs. DMSO-treated BT474-J4 was also observed, implying a further enrichment of lapatinib-resistant cells or enhanced resistance mechanisms during exposure. We then utilized another dataset (GSE69226) 22 to analyze expression changes of cytokines in LC-2/ad DR (a dovitinib-resistant lung adenocarcinoma cell line) vs. LC-2/ad (a dovitinib-sensitive lung adenocarcinoma cell line). Five of 18 (27.8%) coCytokines showed significant differential expression across these two cell lines ( Figure 6E).…”

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

“…Dovitinib demonstrated also nanomolar activity againts RET; accordingly, it inhibited proliferation of CCDC6-RET fusion-positive LC-2/ad lung carcinoma cells with an IC 50 of 200 nM (Kang et al 2015). SRC activation was associated to resistance to Dovitinib in these cells (Kang et al 2015). Finally, daily PO dovitinib at 30 mg/kg reduced growth of LC-2/ad xenografts (Kang et al 2015).…”

“…SRC activation was associated to resistance to Dovitinib in these cells (Kang et al 2015). Finally, daily PO dovitinib at 30 mg/kg reduced growth of LC-2/ad xenografts (Kang et al 2015). …”