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

Autor: James S. Blachly, Shelley Orwick, Jordan N. Skinner, Steven Sher, Katie Williams, Matthew Cannon, Amy Lehman, Daniel Canfield, Lindsey T. Brinton, Pu Zhang, Bonnie K. Harrington, Rosa Lapalombella, Casey Cempre, John C. Byrd, Mukul Govande, Larry Beaver, Ronni Wasmuth
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_treatment
Mice
SCID
Targeted therapy
Gene Knockout Techniques
chemistry.chemical_compound
fluids and secretions
0302 clinical medicine
hemic and lymphatic diseases
Medicine
CRISPR
Midostaurin
FLT3
Sulfonamides
Aniline Compounds
Hematology
Myeloid leukemia
Gilteritinib
hemic and immune systems
lcsh:Diseases of the blood and blood-forming organs
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Synergy
Leukemia
Myeloid
Acute
Proto-Oncogene Proteins c-bcl-2
Oncology
Pyrazines
030220 oncology & carcinogenesis
embryonic structures
Female
Rapid Communication
BCL2
medicine.medical_specialty
Combination therapy
Antineoplastic Agents
lcsh:RC254-282
Venetoclax
03 medical and health sciences
In vivo
Cell Line
Tumor
Internal medicine
Animals
Humans
Protein Kinase Inhibitors
Molecular Biology
Acute myeloid leukemia
lcsh:RC633-647.5
business.industry
Genetic Therapy
Bridged Bicyclo Compounds
Heterocyclic
Staurosporine
030104 developmental biology
fms-Like Tyrosine Kinase 3
chemistry
Cancer research
CRISPR-Cas Systems
business
Zdroj: Journal of Hematology & Oncology
Journal of Hematology & Oncology, Vol 13, Iss 1, Pp 1-10 (2020)
ISSN: 1756-8722
Popis: 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.
Databáze: OpenAIRE
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