| RRC ID |
68808
|
| 著者 |
Ota Y, Yoda H, Inoue T, Watanabe T, Shinozaki Y, Takatori A, Nagase H.
|
| タイトル |
Targeting anaplastic lymphoma kinase (ALK) gene alterations in neuroblastoma by using alkylating pyrrole-imidazole polyamides.
|
| ジャーナル |
PLoS One
|
| Abstract |
Anaplastic lymphoma kinase (ALK) aberration is related to high-risk neuroblastomas and is an important therapeutic target. As acquired resistance to ALK tyrosine kinase inhibitors is inevitable, novel anti-ALK drug development is necessary in order to overcome potential drug resistance against ATP-competitive kinase inhibitors. In this study, to overcome ALK inhibitor resistance, we examined the growth inhibition effects of newly developed ALK-targeting pyrrole-imidazole polyamide CCC-003, which was designed to directly bind and alkylate DNA within the F1174L-mutated ALK gene. CCC-003 suppressed cell proliferation in ALK-mutated neuroblastoma cells. The expression of total and phosphorylated ALK was downregulated by CCC-003 treatment but not by treatment with a mismatch polyamide without any binding motif within the ALK gene region. CCC-003 preferentially bound to the DNA sequence with the F1174L mutation and significantly suppressed tumor progression in a human neuroblastoma xenograft mouse model. Our data suggest that the specific binding of CCC-003 to mutated DNA within the ALK gene exerts its anti-tumor activity through a mode of action that is distinct from those of other ALK inhibitors. In summary, our current study provides evidence for the potential of pyrrole-imidazole polyamide ALK inhibitor CCC-003 for the treatment of neuroblastoma thus offering a possible solution to the problem of tyrosine kinase inhibitor resistance.
|
| 巻・号 |
16(9)
|
| ページ |
e0257718
|
| 公開日 |
2021-1-1
|
| DOI |
10.1371/journal.pone.0257718
|
| PII |
PONE-D-20-38161
|
| PMID |
34591871
|
| PMC |
PMC8483358
|
| MeSH |
Anaplastic Lymphoma Kinase / genetics*
Anaplastic Lymphoma Kinase / metabolism*
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Down-Regulation
Drug Resistance, Neoplasm / drug effects*
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Imidazoles / administration & dosage*
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology
Mice
Mutation
Neuroblastoma / drug therapy*
Neuroblastoma / genetics
Neuroblastoma / metabolism
Nylons / chemical synthesis
Nylons / chemistry
Phosphorylation / drug effects
Pyrroles / chemistry*
Xenograft Model Antitumor Assays
|
| IF |
2.74
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3-CL1(RCB4474) |
