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Cancer Research Is Leading the Way
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Bruton’s tyrosine kinase (BTK) is a crucial enzyme for B-cell differentiation, proliferation, and survival (Pal Singh, Dammeijer, and Hendriks 2018). In the context of B-cell malignancies, including NHL, inhibition of BTK alters cytokine signaling resulting in decreased proliferation and impaired cell migration (Pal Singh, Dammeijer, and Hendriks 2018). The earliest evidence in support of clinical efficacy of BTK inhibitors was generated in a comparative oncology trial in canines with spontaneous lymphoma (Honigberg et al. 2010). This particular trial was unique in that there were no suitable mouse models to utilize for preclinical efficacy evaluation, as mouse models of B-cell lymphoma had impaired B-cell receptor signaling that was dissimilar to humans and canines (Thamm 2019). Thus, the canine lymphoma trial was the first in vivo study to demonstrate proof-of-concept that BTK inhibition could lead to measurable antitumor responses in lymphoma (Honigberg et al. 2010). Additionally, this study was critical for the development of pharmacodynamic assays used in subsequent human clinical trials to ensure adequate drug exposures (Honigberg et al. 2010). The results of this canine oncology trial directly informed human clinical trials, leading to FDA approval for ibrutinib use in several B-cell malignancies (Thamm 2019).
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
X-linked agammaglobulinemia (XLA) results from mutations of the Bruton's tyrosine kinase (BTK) gene. BTK is located on the X chromosome and regulates signaling through the pre-B-cell receptor (pre-BCR) and the BCR. BTK deficiency results in a block at the pro-B to pre-B cell stage in B-cell differentiation in the bone marrow. Accordingly, patients with XLA have a severe reduction or absence of circulating B cells, associated with profound deficiency of all immunoglobulin isotypes. A similar phenotype can also be observed in patients with autosomal recessive forms of agammaglobulinemia, due to mutations of the mu (μ) heavy-chain gene; of the Igα, Igβ, and V pre-B components of the pre-BCR; or of the adaptor molecule B-cell linker protein, which is also involved in pre-BCR-mediated signaling.
Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
X-linked agammaglobulinaemia (XLA) was described in 1952 by Bruton. It is caused by mutations in the BTK (Bruton tyrosine kinase) gene, located at Xq22. BTK is essential for B-cell development and is involved in signalling.
Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness
Published in OncoImmunology, 2022
Robby Barnestein, Loïck Galland, Laura Kalfeist, François Ghiringhelli, Sylvain Ladoire, Emeric Limagne
Another interesting point to highlight concerns Bruton’s tyrosine kinase (BTK) inhibitors. BTK plays a crucial role in oncogenic pathways and is notably known for its involvement in B cell malignancies. Therefore, BTK inhibitors have emerged including ibrutinib, which can inhibit phosphorylation of BTK and efficiently reduce the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive BC cell lines.141 Dubovsky et al. suggested that ibrutinib may also enhance the antitumor immune response by modulating the Th1/Th2 CD4+ T cell ratio.142 Treatment of mice bearing EMT-6 mammary tumors with ibrutinib resulted in a reduced frequency of MDSCs in both the spleen and tumor.143 Varikuti et al. demonstrated that ibrutinib was able to deplete and reprogram MDSCs to mature DCs, which boosts antitumor Th1 immune response and improves infiltration of cytotoxic T lymphocytes due to enhanced tumor-derived antigen presentation to CD8+ T cells.144 A combination of immunotherapy and ibrutinib was shown to suppress tumor growth in preclinical models of TNBC.145 However, a phase 1/2 clinical trial reported limited antitumor activity with a combination of ibrutinib-immunotherapy (durvalumab).146
Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Tony Eight Lin, Li-Chin Sung, Min-Wu Chao, Min Li, Jia-Huei Zheng, Tzu-Ying Sung, Jui-Hua Hsieh, Chia-Ron Yang, Hsueh-Yun Lee, Er-Chieh Cho, Kai-Cheng Hsu
BTK is a member of the Tec-family of non-receptor tyrosine kinases and has essential roles in regulating proliferation, migration, survival, and B-cell homing3. The dysregulation of BTK, therefore, can lead to various haematologic malignancies4,5. However, recent studies have also implicated aberrant BTK signalling in solid cancers6,7. High expression of BTK in glioma can indicate poor survival6. Overexpression of a BTK isoform has been observed in patients with colorectal cancer8,9. BTK is also found to be overexpressed in gastric carcinoma and treatment with a BTK inhibitor can reduce tumour growth10. The involvement of BTK in these solid tumours may be due to its ability to modulate multiple signalling pathways2. Nevertheless, aberrant BTK expression in various malignancies makes it a promising therapeutic target.
Ibrutinib-induced acute kidney injury via interstitial nephritis
Published in Renal Failure, 2021
Csilla Markóth, Ibolya File, Róbert Szász, László Bidiga, József Balla, János Mátyus
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].