Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes

Autor: Johannes Elferich, Mona M.Hosseini, Sherif Abdelhamed, Jason E. McDermott, Brian J. Druker, Ujwal Shinde, Karin D. Rodland, Anupriya Agarwal, Shawn Mahmood, Samuel H. Payne, Monika A. Davare, Tao Liu, Jack W. Singer, Motomi Mori, Andy Kaempf, Stephen E. Kurtz
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Cancer Research
Ruxolitinib
Myeloid
Mice
SCID
chemistry.chemical_compound
Mice
Mice
Inbred NOD
hemic and lymphatic diseases
Child
Aged
80 and over
Kinase
Myeloid leukemia
Hematology
Middle Aged
Leukemia
Leukemia
Myeloid
Acute
medicine.anatomical_structure
Interleukin-1 Receptor-Associated Kinases
Oncology
Female
FLT3 Inhibitor
medicine.drug
Adult
Bridged-Ring Compounds
Adolescent
Article
03 medical and health sciences
Young Adult
Cell Line
Tumor
Nitriles
medicine
Animals
Humans
Benzothiazoles
neoplasms
Protein Kinase Inhibitors
Quizartinib
Aged
business.industry
Phenylurea Compounds
Janus Kinase 2
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Pacritinib
Pyrimidines
chemistry
fms-Like Tyrosine Kinase 3
Mutation
Cancer research
Pyrazoles
business
Zdroj: Leukemia. 32(11)
ISSN: 1476-5551
Popis: Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden. Kinase profiling indicated pacritinib has potent inhibitory activity against IRAK1. Computational modeling combined with site-directed mutagenesis demonstrated high-affinity binding of pacritinib to the IRAK1 kinase domain. Pacritinib exposure reduced IRAK1 phosphorylation in AML cells. A higher percentage of primary AML samples showed robust sensitivity to pacritinib, which inhibits FLT3, JAK2, and IRAK1, relative to FLT3 inhibitor quizartinib or JAK1/2 inhibitor ruxolitinib, demonstrating the importance of IRAK1 inhibition. Pacritinib inhibited the growth of AML cells harboring a variety of genetic abnormalities not limited to FLT3 and JAK2. Pacritinib treatment reduced AML progenitors in vitro and the leukemia burden in AML xenograft model. Overall, IRAK1 contributes to the survival of leukemic cells, and the suppression of IRAK1 may be beneficial among heterogeneous AML subtypes.
Databáze: OpenAIRE
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