Abstract 1047: Dual targeting of CK2 and MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

Abstract

Abstract Genomic defect and Casein Kinase II-mediated hyper-phosphorylation of Ikaros tumor suppressor cause the loss of function of Ikaros, and Ikaros dysfunction is characteristics of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. The increased activation of the PI3K/AKT/mTOR pathway is also observed in HR B-ALL and identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that Ikaros represses MTOR transcription and Ikaros' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances Ikaros activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with Ikaros-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from HR B-ALL. These data suggest that such therapy has the potential to reduce the death rate in HR B-ALL. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies. Citation Format: Chunhua Song, Zheng Ge, Yali Ding, Bihua Tan, Elanora Dovat, Yiping Yang, Chandrika Gowda, Sinisa Dovat. Dual targeting of CK2 and MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1047.