論文 - 詳細
| RRC ID | 67411 |
|---|---|
| 著者 | Kang CW, Jang KW, Sohn J, Kim SM, Pyo KH, Kim H, Yun MR, Kang HN, Kim HR, Lim SM, Moon YW, Paik S, Kim DJ, Kim JH, Cho BC. |
| タイトル | Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma. |
| ジャーナル | Mol Cancer Ther |
| 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 G0-G1 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. |
| 巻・号 | 14(10) |
| ページ | 2238-48 |
| 公開日 | 2015-10-1 |
| DOI | 10.1158/1535-7163.MCT-15-0350 |
| PII | 1535-7163.MCT-15-0350 |
| PMID | 26208525 |
| MeSH | Adenocarcinoma / drug therapy* Adenocarcinoma / enzymology Adenocarcinoma / pathology Adenocarcinoma of Lung Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Apoptosis Benzimidazoles / chemistry Benzimidazoles / pharmacology* Catalytic Domain Cell Cycle Checkpoints Cell Line, Tumor Drug Resistance, Neoplasm* Enzyme Activation HEK293 Cells Humans Inhibitory Concentration 50 Lung Neoplasms / drug therapy* Lung Neoplasms / enzymology Lung Neoplasms / pathology Mice, Nude Models, Molecular Protein Kinase Inhibitors Proto-Oncogene Proteins c-ret / antagonists & inhibitors* Proto-Oncogene Proteins c-ret / chemistry Quinolones / chemistry Quinolones / pharmacology* Tumor Burden / drug effects Xenograft Model Antitumor Assays src-Family Kinases / metabolism |
| IF | 5.615 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | LC-2/ad(RCB0440) |