Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia
Zheng Ge, Chunhua Song, Yali Ding, Bi-Hua Tan, Dhimant Desai, Arati Sharma, Raghavendra Gowda, Feng Yue, Suming Huang, Vladimir S. Spiegelman, Jonathon L. Payne, Mark E. Reeves, Soumya Iyer, Pavan Kumar Dhanyamraju, Yuka Imamura Kawasawa, Daniel Bogush, Yevgeniya Bamme, Yiping Yang, Mario Soliman, Shriya Kane, Elanora Dovat, Joseph Schramm, Tommy Hu, Mary McGrath, Zissis C. Chroneos, Kimberly J. Payne, Chandrika Gowda, Sinisa Dovat
Abstract
Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This 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 Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. 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.