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Targeting CDK11 in Rhabdoid Tumor of the Kidney
Yuki Murakami1,2, Kamhung Lam1, Shinsuke Fukui1
1Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Background:
Rhabdoid tumor of the kidney (RTK) is a highly aggressive pediatric malignancy characterized by biallelic SMARCB1 loss, resulting in aberrant MYC pathway activation and cell cycle regulation. MYC-activated tumors are vulnerable in splicing functions and sensitive to splicing inhibitors. Therefore, in this study, cyclin-dependent kinase 11 (CDK11), which regulates both cell cycle and RNA splicing, was tested as a therapeutic target in RTK.
Methods:
CDK11A/B expression was analyzed using the TARGET-RT database. The therapeutic efficacy of the CDK11 inhibitor OTS964 was evaluated in two RTK cell lines (G401 and JMU-RTK-2) and a JMU-RTK-2 xenograft mouse model. Cytotoxicity, apoptosis, cell cycle, and RNA splicing were examined using the Sulforhodamine B assay, immunoblotting, flow cytometry, and RT-PCR.
Results:
CDK11B, but not CDK11A, was significantly upregulated in RTK and correlated with the poor survival. OTS964 inhibited RTK cell growth in vitro with the IC50 of 33.1 nM (G401) and 19.3 nM (JMU-RTK-2) and significantly prolonged survival in vivo (median survival: 46.5 vs. 37.0 days, p < 0.01) without marked toxicity. Mechanistically, OTS964 induced G2/M cell cycle arrest and p53 upregulation, disrupted RNA splicing via SF3B1 dephosphorylation, and ultimately led to apoptosis through caspase-3 activation.
Conclusions:
CDK11 inhibition by OTS964 effectively suppresses RTK growth through cell cycle arrest and RNA splicing inhibition, leading to apoptosis. OTS964 shows potent anti-tumor activity and tolerability, supporting CDK11 as a promising therapeutic target for RTK and related SMARCB1-deficient cancers.
Insights
Cyclin-dependent kinase 11 (CDK11) inhibition effectively targets rhabdoid tumor of the kidney (RTK) by halting cell cycle progression and RNA splicing. This approach shows promise for treating pediatric cancers with SMARCB1 loss.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Rhabdoid tumor of the kidney (RTK) is an aggressive pediatric cancer linked to SMARCB1 loss, MYC pathway activation, and cell cycle dysregulation.
- MYC-activated tumors exhibit vulnerabilities in RNA splicing, suggesting potential therapeutic targets like splicing inhibitors.
Purpose of the Study:
- To investigate cyclin-dependent kinase 11 (CDK11) as a therapeutic target in RTK, given its role in cell cycle and RNA splicing.
- To evaluate the efficacy of the CDK11 inhibitor OTS964 in preclinical RTK models.
Main Methods:
- Analyzed CDK11A/B expression in RTK using the TARGET-RT database.
- Assessed OTS964's therapeutic efficacy in RTK cell lines and a xenograft mouse model.
- Examined cytotoxicity, apoptosis, cell cycle, and RNA splicing using various assays (SRB, immunoblotting, flow cytometry, RT-PCR).
Main Results:
- CDK11B was upregulated in RTK and correlated with poor survival; CDK11A was not.
- OTS964 demonstrated potent in vitro cytotoxicity (IC50: 33.1 nM, 19.3 nM) and significantly prolonged survival in vivo (p < 0.01) with minimal toxicity.
- OTS964 induced G2/M cell cycle arrest, p53 upregulation, disrupted RNA splicing via SF3B1 dephosphorylation, and triggered apoptosis.
Conclusions:
- CDK11 inhibition by OTS964 effectively suppresses RTK growth via cell cycle arrest and RNA splicing inhibition, culminating in apoptosis.
- OTS964 exhibits potent anti-tumor activity and good tolerability, establishing CDK11 as a promising therapeutic target for RTK and SMARCB1-deficient cancers.
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