| 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
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
