Abstract 6959: CK2 inhibition exhibits synergistic effect with KIT inhibitors in acute lymphoblastic leukemia

Abstract Survival for pre-B cell Acute lymphoblastic leukemia (B-ALL) has significantly improved, but High Risk (HR) subgroups continue to result in increased death for pediatric oncology patients. Novel treatment strategies are required to conquer chemotherapy resistance and improve life expectancy for HR B-ALL. Deletion of IKZF1, resulting in decreased IKAROS function, is a feature of high-risk B-ALL that is associated with resistance to chemotherapy and a poor prognosis. Casein kinase 2 (CK2) is a protein kinase upregulated in B-ALL, which phosphorylates IKAROS and reduces Ikaros DNA binding affinity. This results in a loss of IKAROS-mediated transcriptional regulation in B-ALL patients. Previous studies have shown that pharmacologic inhibition of CK2 with CX-4945 recovers IKAROS function as a transcriptional regulator. Receptor tyrosine kinase c-KIT is transcriptionally regulated by IKAROS and is often upregulated in B-ALL. The purpose of this study was to determine whether restoration of IKAROS function as c-KIT repressor via CX-4945 would act in a synergistic manner with c-KIT inhibitor imatinib in B-ALL. B-ALL cells were treated with imatinib over 72-hours to demonstrate the half-maximal inhibitory concentration (IC50). The IC50 was used to determine the range of the concentration of imatinib to be used in association with CX-4945 in a 72-hour synergy analysis of cytotoxicity. Cell viability was determined using WST-1 cell proliferation assay. The data was analyzed using Calcusyn and synergy was specified as a combination index below 0.85. The study was repeated with several different drug concentrations to establish a more precise range of synergy. The cytotoxicity of single drug c-KIT inhibitor, Imatinib, in Nalm6 B-ALL produced an IC50 of 25uM while CK2 inhibitor CX-4945 has IC50 of 4uM. When a combination was administered with a constant dose of CX-4945 at 4uM and different concentrations of imatinib, synergy was detected at several dose combinations. In conclusion, our results demonstrate that CK2 inhibitor, CX-4945, and c-KIT inhibitor, imatinib, exhibit a synergistic therapeutic effect on B-ALL cells. Presented data provide a rational for the use of combination therapy with CK2 inhibitors and imatinib for treatment of high-risk B-ALL, including Philadelphia positive (Ph+) B-ALL. Citation Format: Katarina Dovat, Daniel Bogush, Julia Randazzo, Marjon Rafie, Stephanie Buczkowski, Rabab Husain, Joseph Schramm, Yali Ding, Chingakham Singh, Dhimant Desai. CK2 inhibition exhibits synergistic effect with KIT inhibitors in 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 6959.