The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia
| Autor: | Fanny Krantz, Dolors Colomer, Raquel Izumi, Jennifer A. Woyach, Bonnie K. Harrington, Arnau Montraveta, Sarah E. M. Herman, Carsten Utoft Niemann, Fabienne McClanahan, Amy J. Johnson, Lisa L. Smith, Todd Covey, Brian J. Lannutti, Roger G. Ulrich, Helena Mora-Jensen, Rose Mantel, Adrian Wiestner, Allard Kaptein, Michael Gulrajani, John C. Byrd |
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| Rok vydání: | 2016 |
| Předmět: |
Genetically modified mouse
Cancer Research Adoptive cell transfer Chronic lymphocytic leukemia Apoptosis Mice Transgenic Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Piperidines immune system diseases In vivo hemic and lymphatic diseases Proto-Oncogene Proteins Antineoplastic Combined Chemotherapy Protocols medicine Agammaglobulinaemia Tyrosine Kinase Bruton's tyrosine kinase Animals Humans Protein Kinase Inhibitors biology business.industry Adenine Protein-Tyrosine Kinases medicine.disease Adoptive Transfer Leukemia Lymphocytic Chronic B-Cell Xenograft Model Antitumor Assays Leukemia Disease Models Animal Pyrimidines Oncology chemistry 030220 oncology & carcinogenesis Ibrutinib Pyrazines Immunology Benzamides biology.protein Cancer research Acalabrutinib Pyrazoles business 030215 immunology |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 23(11) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water. Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle. Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer Res; 23(11); 2831–41. ©2016 AACR. |
| Databáze: | OpenAIRE |
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