Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia

Journal of Hematology & Oncology

Amy Lehman¹  Bonnie Harrington²  Mukul Govande³  Matthew Cannon⁴  Shelley Orwick⁴  Pu Zhang⁴  Daniel Canfield⁴  Lindsey T. Brinton⁴  Katie Williams⁴  Casey Cempre⁴  Ronni Wasmuth⁴  Steven Sher⁴  Larry Beaver⁴  Jordan Skinner⁴  John C. Byrd⁵  Rosa Lapalombella⁶  James S. Blachly⁷ 

[1] Center Biostatistics, The Ohio State University, Columbus, OH, USA;College of Veterinary Medicine, Michigan State University, Lansing, MI, USA;Department of Biomedical Engineering, The Ohio State University, Room 455C, OSUCCC Building, 410 West 12th Avenue, 43210, Columbus, OH, USA;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA;College of Pharmacy, The Ohio State University, Columbus, OH, USA;College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA;Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA;Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA;Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA;Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA;

关键词: Gilteritinib;    Midostaurin;    Synergy;    Combination therapy;    FLT3;    BCL2;    Venetoclax;    Acute myeloid leukemia;   

DOI  :  10.1186/s13045-020-00973-4

来源: Springer

【 摘 要 】

Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.

【 授权许可】

CC BY