論文 - 詳細
| RRC ID | 86417 |
|---|---|
| 著者 | Kim JM, Nam AR, Oh KS, Bang JH, Jeong Y, Choo SY, Kim HJ, Lee SI, Yoon J, Kim TY, Oh DY. |
| タイトル | Fadraciclib, a CDK2/CDK9 inhibitor, shows efficacy in biliary tract cancer and synergistic potential with olaparib and JQ1 based on MCL1 expression. |
| ジャーナル | Cell Commun Signal |
| Abstract |
BACKGROUND:Targeting CDKs has emerged as a significant strategy in cancer drug development. While CDK4/6 inhibitors have proven effective in several cancers, CDK2 and CDK9 inhibitors are under clinical trials. In biliary tract cancer (BTC), CDK2 and CDK9 expression levels are elevated compared to normal tissue. CDK9, a transcriptional CDK, regulates RNAPII, promoting the transcription of oncogenes, such as MCL1. Aberrant CDK activation contributes to cancer progression and apoptosis evasion in BTC. Notably, MCL1 is frequently amplified in intrahepatic cholangiocarcinoma (16-21%), supporting the therapeutic potential of CDK2 and CDK9. However, targeting CDK2/9 in BTC has not yet been explored. This study aimed to evaluate CDK2/9 inhibition and develop possible biomarker strategies in BTC. METHODS:Nine BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1196, SNU2670, SNU2773, TFK1, and HUCCT1) were used. Fadraciclib (CDK2/9 inhibitor), olaparib (PARP inhibitor), and JQ1 (BRD4 inhibitor) were used. Anti-cancer effects were evaluated using MTT assay, colony formation assay, annexin-V assay, and cell cycle analysis. HR-mediated DNA damage repair was assessed using foci formation assay and DRGFP assay. Combination therapies were evaluated in vitro and in vivo. RESULTS:Fadraciclib was more effective in MCL1-High cells, reducing RNAPII phosphorylation and MCL1. Fadraciclib also inhibited HR gene transcription. Fadraciclib-olaparib combination showed synergy in MCL1-High cells and xenograft models. Conversely, in MCL1-Low cells, Fadraciclib upregulated BRD4, restoring RNAP II activity and oncogenes transcription. Combination of fadraciclib-JQ1 suppressed this restoration and showed synergy in vitro and in vivo. CONCLUSIONS:MCL1-High BTCs are sensitive to CDK2/9 inhibition and benefit from combination with PARP inhibitor. In MCL1-Low BTCs, combining CDK2/9 inhibitor and BRD4 inhibitor may represent an optimal strategy for new drug development. |
| 巻・号 | 23(1) |
| ページ | 530 |
| 公開日 | 2025-12-17 |
| DOI | 10.1186/s12964-025-02521-4 |
| PII | 10.1186/s12964-025-02521-4 |
| PMID | 41408267 |
| PMC | PMC12709703 |
| MeSH | Animals Azepines* / pharmacology Azepines* / therapeutic use Biliary Tract Neoplasms* / drug therapy Biliary Tract Neoplasms* / metabolism Biliary Tract Neoplasms* / pathology Cell Line, Tumor Cell Proliferation / drug effects Cyclin-Dependent Kinase 2* / antagonists & inhibitors Cyclin-Dependent Kinase 2* / metabolism Cyclin-Dependent Kinase 9* / antagonists & inhibitors Cyclin-Dependent Kinase 9* / metabolism Drug Synergism Gene Expression Regulation, Neoplastic / drug effects Humans Mice Mice, Nude Myeloid Cell Leukemia Sequence 1 Protein* / genetics Myeloid Cell Leukemia Sequence 1 Protein* / metabolism Phthalazines* / pharmacology Phthalazines* / therapeutic use Piperazines* / pharmacology Piperazines* / therapeutic use Protein Kinase Inhibitors* / pharmacology Triazoles* / pharmacology Triazoles* / therapeutic use Xenograft Model Antitumor Assays |
| IF | 4.344 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) TFK-1(RCB2537) |