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Mol Cancer ; 17(1): 57, 2018 02 19.
Article in English | MEDLINE | ID: mdl-29455639

ABSTRACT

Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/metabolism , Cell Transformation, Neoplastic/metabolism , Leukemia, B-Cell/etiology , Leukemia, B-Cell/metabolism , Lymphoma, B-Cell/etiology , Lymphoma, B-Cell/metabolism , Agammaglobulinaemia Tyrosine Kinase/chemistry , Agammaglobulinaemia Tyrosine Kinase/genetics , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Lymphocytes/pathology , Biomarkers, Tumor , Bone Marrow , Cell Differentiation/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Leukemia, B-Cell/drug therapy , Leukemia, B-Cell/pathology , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Lymphopoiesis/ethics , Molecular Targeted Therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Signal Transduction/drug effects , Treatment Outcome , Tumor Microenvironment
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