Abstract 1906: Novel treatment: CDK11 inhibition in rhabdoid tumor of the kidney.

Abstract Rhabdoid tumor of the kidney (RTK) is an aggressive pediatric malignancy with extremely poor outcomes despite extensive treatment. Its high treatment resistance and disease relapses necessitates a search for new therapeutic strategies. RTK is marked by the loss of SMARCB1 gene, leading to downstream dysfunctions in cell cycle, cell proliferation, and RNA splicing. Cyclin dependent kinases (CDKs) are known to regulate these processes, with several CDK inhibitors already being used in cancer treatment. CDK11’s known function in regulating cell cycle and RNA splicing via splicing factor SF3B1 and its overexpression in various cancers makes it a potential therapeutic target. In this study, we evaluated the therapeutic potential of CDK11 inhibition in RTK. Based on the Therapeutically Applicable Research To Generate Effective Treatments (TARGET)-RT database, RTK tissues (n = 63) have significantly higher CDK11 expression compared to normal kidney tissues (n = 6). We also confirmed higher CDK11 protein expression in two RTK cell lines (G401 and JMU-RTK-2) than in human embryonic kidney cells (HEK293) (p = 0.05, 0.13, respectively). A CDK11 inhibitor, OTS964, showed significant dose-dependent cytotoxicity with IC50 of 33.1 nM in G401 and 19.3 nM in JMU-RTK-2. Next, we treated nude mice engrafted with JMU-RTK-2 tumors with 25 mg/kg of OTS964 or vehicle control. OTS964 monotherapy significantly prolonged survival (median survival: 46.5 days vs 37.0 days) and suppressed tumor progression (p = 0.002) without clinical signs of toxicity. Finally, we investigated OTS964’s mechanisms of action. OTS964 treatment at IC80 of 80 nM (G401) and 30 nM (JMU-RTK-2) significantly increased expression of cleaved PARP, cleaved caspase-3, and p53. G2/M cycle arrest was demonstrated at 8 hours (G401) and 12 hours (JMU-RTK-2). OTS964 is known to inhibit phosphorylation of the splicing factor SF3B1, a core component of the spliceosome, thereby regulating RNA splicing. We confirmed SF3B1 inhibition by increased accumulation of the unspliced transcript DNAJB1, a known SF3B1-dependent transcript. In conclusion, our data demonstrated the therapeutic efficacy of CDK11 inhibition in RTK. CDK11 inhibition using OTS964 suppressed RTK cell growth and prolonged survival in mouse xenograft model. OTS964 induced apoptosis via caspase-3 activation with G2/M cell cycle arrest, p53 upregulation, and RNA splicing disruption via SF3B1 inhibition. In future studies, we plan to investigate synergistic combination of CDK11 inhibition with existing therapies. Citation Format: Kamhung Lam, Yuki Murakami, Shinsuke Fukui, Elizabeth Helmke, Noriko Satake. Novel treatment: CDK11 inhibition in rhabdoid tumor of the kidney abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1906.