Abstract 4004: Targeting drug-resistant acute myeloid leukemia (AML) cells using novel casein kinase II (CK2) inhibitor

Abstract Introduction: Protein Kinase CK2 level and activity are high in Acute Myeloid Leukemia (AML) stem cells. Genetic inhibition of CK2 promotes apoptosis and shows synergistic cytotoxic activity with cytotoxic therapy. Here we report the anti-leukemia efficacy of a novel and potent small molecule inhibitor of CK2, BMS-135, in AML mouse models. Methods: AML cell lines (n=8) and primary AML cells (n=3) representing various AML genetic subtypes (MLL rearranged, FLT3-ITD, TP53 mutation) were tested in vitro. Cells were treated with serial dilution of BMS-135 for 24 to 48hrs, and cell viability was measured using calorimetric cell viability (WST) assay. Similarly, treated cells were analyzed for cell cycle distribution, apoptosis, and colony formation. We measured the mRNA and protein levels of known CK2 targets. RNA sequencing and gene expression analysis was done to evaluate gene expression changes following treatment with BMS-135. Cell line-derived xenograft and patient-derived xenograft of AML were treated with BMS-135 at a dose of 7.5mg/kg oral gavage twice daily for 21 days or vehicle. Results: Combined in vitro and in vivo experiments establish the efficacy of BMS-135. Cytotoxicity at inhibitory concentrations of 30-800nM, G0-G1 cell cycle arrest, increased apoptosis, and poor colony formation following treatment were noted consistently in all cells. Single-drug treatment with BMS-135 achieved 50-80% leukemia inhibition and significantly prolonged survival in treated mice after 3 weeks of therapy. Following in vivo treatment with BMS-135, we confirmed the inhibition of known CK2 targets (AKT, PI3K, Bcl-xL) in the bone marrow and spleen AML cells. No significant myelosuppression or organ toxicity was noted in tumor-bearing mice following 3 weeks of treatment when compared to vehicle-treated mice. BMS-135 shows synergistic cytotoxic activity with daunorubicin and cytarabine. Conclusions: Selective inhibitor of CK2 is well tolerated and shows superior in vivo efficacy and target inhibition in a series of AML cells and xenografts. BMS-135 works synergistically with cytotoxic agents like daunorubicin and cytarabine. These results support further pre-clinical characterization and clinical development of BMS-135 for treating AML in combination with cytotoxic therapy. Citation Format: Koby Duke, Katherine Mercer, Rajesh Rajaiah, Muhammad Daniyal, Yi Qiu, Ashok Purandare, Yasin Uzun, Lijun Zhang, Morgann Klink, Chandrika Gowda. Targeting drug-resistant acute myeloid leukemia (AML) cells using novel casein kinase II (CK2) inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4004.