Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
Lindsey T. Brinton, Pu Zhang, Katie Williams, Daniel Canfield, Shelley Orwick, Steven Sher, Ronni Wasmuth, Larry Beaver, Casey B. Cempre, Jordan Skinner, Matthew Cannon, Mukul Govande, Bonnie K. Harrington, Amy Lehman, John C. Byrd, Rosa Lapalombella, James S. Blachly
Abstract
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.