Abstract 1617: Targeting CDK11 in high-risk B cell acute lymphoblastic leukemia
Authors: Yuki Murakami, Elizabeth Helmke, Kamhung Lam, John McPherson, Noriko Satake
Journal: Cancer Research (2025)

Abstract The outcome for children with high-risk B-cell acute lymphoblastic leukemia (B-ALL) is poor. Disease relapse is speculated to be due to leukemia cells escaping treatment. Cyclin-dependent kinases (CDKs) have been demonstrated to be therapeutic targets in many cancers, and inhibitors of some CDKs have already been developed in the clinic. For example, CDK4/6 inhibitors have been used for treating patients with breast cancer, and a CDK2 inhibitor is being evaluated in a clinical trial for solid cancers. CDK11, known as a direct splicing regulator in CDKs, is overexpressed in several types of tumors, such as osteosarcoma and multiple myeloma and is shown to be a therapeutic target in many cancers. In B-ALL, dysregulated RNA splicing is linked to drug resistance and disease relapse. In this study, we investigated the therapeutic potential of CDK11 inhibition in B-ALL. CDK11 protein expression was significantly higher in B-ALL cell lines (Reh and JM1) and 26 primary B-ALL samples (13 each for standard-risk and high-risk), regardless of the risk group, than in normal B-cells and hematopoietic stem cells. A CDK11 inhibitor, OTS964, showed significant dose-dependent cytotoxicity in the cell lines with IC50 of 22nM and 14nM. OTS964 also showed significant cytotoxicity in three harvested high-risk patient-derived xenograft (PDX) samples with high CDK11 expression. OTS964 did not show cytotoxicity in normal B-cells at the same tested concentrations. OTS964 is known to regulate RNA splicing by the deactivation of SF3B1, a core component of the spliceosome. We confirmed OTS964 rapidly inhibited the phosphorylation of SF3B1, which is highly activated in B-ALL. G2/M cell cycle arrest and apoptosis induction were observed 24 hours after treatment in B-ALL cell lines. OTS964 induced p53 expression, which regulates cell cycle and apoptosis, as early as 1 hour after treatment. Furthermore, OTS964 induced short pro-apoptotic spliced isoforms, instead of anti-apoptotic forms, in MCL-1, a gene within the BCL-2 family, as early as 3 hours after treatment. The combination of splicing modulators and BCL-2 inhibitors shows synergism by each drug inhibiting different BCL-2 family genes. Therefore, we tested the combination with OTS964 and navitoclax, a BCL-2 inhibitor inhibiting BCL-2, BCL-x, and BCL-w in BCL-2 family genes. As expected, the combination showed strong synergisms in B-ALL cell lines and in the three harvested high-risk PDX samples. It was also effective in the sample with low CDK11 expression in vitro. Our in vivo study of the combination therapy is ongoing. In conclusion, these data demonstrated the therapeutic potential of CDK11 inhibition in high-risk B-ALL. OTS964 rapidly deactivated SF3B1 and induced the pro-apoptotic forms of MCL-1, leading to cell apoptosis. Additionally, the new combination with OTS964 and navitoclax showed synergism. In future studies, we will investigate how CDK11 inhibition regulates splicing factors other than SF3B1. Citation Format: Yuki Murakami, Elizabeth Helmke, Kamhung Lam, John McPherson, Noriko Satake. Targeting CDK11 in high-risk B cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1617.