Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
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Synergistic effect of BCL2 and FLT3 co‑inhibition in acute myeloid leukemia Lindsey T. Brinton1, Pu Zhang1, Katie Williams1, Daniel Canfield1, Shelley Orwick1, Steven Sher1, Ronni Wasmuth1, Larry Beaver1, Casey Cempre1, Jordan Skinner1, Matthew Cannon1, Mukul Govande2, Bonnie Harrington3, Amy Lehman4, John C. Byrd1,5,6,7, Rosa Lapalombella1,7*† and James S. Blachly1,7,8†
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. Keywords: Gilteritinib, Midostaurin, Synergy, Combination therapy, FLT3, BCL2, Venetoclax, Acute myeloid leukemia Acute myeloid leukemia (AML) is a molecularly complex disease due to the presence of multiple genetic abnormalities that influence prognosis and therapy outcome [1]. Several approaches for improving outcomes in AML patients have been investigated to date with moderate success. Internal tandem duplications (ITDs) in the FMSlike tyrosine kinase 3 (FLT3) gene are among the most common abnormalities seen in younger adult AML and are present in approximately 30% of patients; it leads to constitutive FLT3 kinase activity and downstream activation of signal transducer and activator of transcription 5 (STAT5) [2, 3]. The presence of FLT3-ITD mutations at a high ITD/wild-type ratio has prognostic value both as a *Correspondence: [email protected] † The authors Rosa Lapalombella and James S. Blachly have contributed equally to this work. 1 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA Full list of author information is available at the end of the article
risk factor for relapse and poor survival in AML patients [4]. FLT3-targeting inhibitors that block constitutively active FLT3 kinase and downstream proliferative signaling have been developed and tested clinically; these include midostaurin and gilteritinib [5–9]. Despite the initial success at prolonging survival rates compared to prior standards therapies, available follow-up data with FLT3 inhibitor therapies show that this class of
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