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 |
Externí odkaz: |