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Fadraciclib, a CDK2/CDK9 inhibitor, shows efficacy in biliary tract cancer and synergistic potential with olaparib
Jae-Min Kim1,2, Ah-Rong Nam1, Kyoung-Seok Oh1
1Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.
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.
Insights
Targeting CDK2/9 with fadraciclib shows promise in biliary tract cancer (BTC). MCL1-High BTCs benefit from combination with PARP inhibitors, while MCL1-Low BTCs may respond to CDK2/9 and BRD4 inhibitor combinations.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin-dependent kinases (CDKs) are crucial in cancer development, with CDK4/6 inhibitors approved for certain cancers.
- CDK2 and CDK9 are implicated in biliary tract cancer (BTC) progression, showing elevated expression and promoting oncogene transcription (e.g., MCL1).
- Targeting CDK2/9 presents a potential therapeutic strategy for BTC, particularly given MCL1 amplification in intrahepatic cholangiocarcinoma.
Purpose of the Study:
- To evaluate the efficacy of CDK2/9 inhibition in BTC.
- To explore potential biomarker strategies for CDK2/9 targeted therapies.
- To investigate combination therapies involving CDK2/9 inhibitors in BTC.
Main Methods:
- Utilized nine BTC cell lines for in vitro studies.
- Administered fadraciclib (CDK2/9 inhibitor), olaparib (PARP inhibitor), and JQ1 (BRD4 inhibitor).
- Assessed anti-cancer effects via MTT, colony formation, annexin-V assays, cell cycle analysis, and DNA damage repair assays; evaluated combination therapies in vitro and in vivo.
Main Results:
- Fadraciclib demonstrated greater efficacy in MCL1-High BTC cells, reducing RNAPII phosphorylation and MCL1 levels, and inhibiting HR gene transcription.
- Combination of fadraciclib and olaparib showed synergistic effects in MCL1-High cells and xenograft models.
- In MCL1-Low cells, fadraciclib upregulated BRD4, which was suppressed by the fadraciclib-JQ1 combination, leading to synergistic anti-cancer effects.
Conclusions:
- MCL1-High BTCs are sensitive to CDK2/9 inhibition, with combination therapy using PARP inhibitors showing significant benefit.
- For MCL1-Low BTCs, a combination strategy involving CDK2/9 and BRD4 inhibitors may offer an optimal approach for new drug development.
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