2. Academic Validation
  3. Targeting CDK11 in Rhabdoid Tumor of the Kidney

Targeting CDK11 in Rhabdoid Tumor of the Kidney

  • Cancers (Basel). 2026 Jan 14;18(2):261. doi: 10.3390/cancers18020261.
Yuki Murakami 1 2,  Kamhung Lam 1,  Shinsuke Fukui 1,  Elizabeth Helmke 1,  Kenneth A Iczkowski 3,  Yueju Li 4,  Noriko Satake 1 2
Affiliations

Affiliations

  • 1 Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
  • 2 Comprehensive Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
  • 3 Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
  • 4 Department of Public Health Sciences, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
PMID: 41595181 DOI: 10.3390/cancers18020261
Abstract

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.

Keywords

CDK11 inhibitor; RNA splicing; apoptosis; cell cycle; rhabdoid tumor.

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