# Targeting CDK11 in Rhabdoid Tumor of the Kidney

## TL;DR

This study shows that inhibiting CDK11 with OTS964 effectively stops the growth of rhabdoid tumor of the kidney in cell and mouse models, offering a new treatment possibility.

## Contribution

The study identifies CDK11 as a novel therapeutic target for RTK and demonstrates the efficacy of OTS964 in preclinical models.

## Key findings

- OTS964 inhibited RTK cell growth in vitro with IC50 values of 33.1 nM and 19.3 nM.
- OTS964 prolonged survival in a mouse model without significant toxicity.
- OTS964 induced G2/M cell cycle arrest and apoptosis through RNA splicing disruption.

## Abstract

Rhabdoid tumor of the kidney (RTK) is a rare and aggressive childhood cancer with very poor survival. Current treatments are limited, and new therapies are urgently needed. CDK11 controls both cell cycle and RNA splicing. CDK11 was highly expressed in RTK and associated with poor patient outcomes. A CDK11 inhibitor OTS964 inhibited tumor cell growth in RTK cells and our mouse model. OTS964 induced cell cycle arrest and disrupted RNA splicing, leading to cell death. Importantly, in our mouse model, OTS964, as a single drug treatment, even at low doses, showed significant efficacy, with no major side effects. These results suggest that blocking CDK11 could become a promising new treatment strategy for RTK and similar cancers with SMARCB1 loss.

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.