論文 - 詳細
| RRC ID | 65939 |
|---|---|
| 著者 | Ogura H, Nagatake-Kobayashi Y, Adachi J, Tomonaga T, Fujita N, Katayama R. |
| タイトル | TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity. |
| ジャーナル | Sci Rep |
| Abstract |
ROS1 rearrangement is observed in 1-2% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in ROS1-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation-mediated crizotinib-resistance in ROS1-fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by N-ethyl-N-nitrosourea mutagenesis screening using CD74-ROS1-expressing Ba/F3 cells. Two resistant cell lines with CD74-ROS1 F2004V or F2075C mutations, which are homologous to ALK F1174 or F1245 mutations, survived in the presence of a low dose of ROS1-TKI. Removal of ROS1-TKI from these TKI-addicted cells induced excessive activation of ROS1 tyrosine kinase followed by apoptosis. We succeeded in recapturing the TKI-addicted phenotype using doxycycline-inducible CD74-ROS1 mutant over-expression in Ba/F3 cells, suggesting that excessive ROS1 oncogenic signaling itself induced apoptosis instead of cell growth. Phosphoproteomic analysis and high-throughput inhibitor screening revealed that excessive ROS1 signaling in the TKI-addicted cells phosphorylated or activated apoptosis-related molecules such as FAF1 or p38. Collectively, our findings partly clarify molecular mechanisms of excessive ROS1 oncogenic signaling that mediates paradoxical induction of apoptosis. |
| 巻・号 | 7(1) |
| ページ | 5519 |
| 公開日 | 2017-7-17 |
| DOI | 10.1038/s41598-017-05736-9 |
| PII | 10.1038/s41598-017-05736-9 |
| PMID | 28717217 |
| PMC | PMC5514057 |
| MeSH | Anilides / pharmacology Antigens, Differentiation, B-Lymphocyte / genetics Antigens, Differentiation, B-Lymphocyte / metabolism Apoptosis / drug effects* Cell Line, Tumor Doxycycline / pharmacology Drug Resistance, Neoplasm / genetics Ethylnitrosourea / pharmacology Histocompatibility Antigens Class II / genetics Histocompatibility Antigens Class II / metabolism Humans Imidazoles / pharmacology Mutagenesis, Site-Directed Phosphopeptides / analysis Protein Kinase Inhibitors / pharmacology* Protein Structure, Tertiary Protein-Tyrosine Kinases / chemistry Protein-Tyrosine Kinases / genetics Protein-Tyrosine Kinases / metabolism* Proto-Oncogene Proteins / chemistry Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Pyridines / pharmacology Signal Transduction / drug effects Tandem Mass Spectrometry p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors p38 Mitogen-Activated Protein Kinases / metabolism |
| IF | 3.998 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 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 | Ba/F3(RCB0805) |