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  • Review Article
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Targeting Bruton's tyrosine kinase in B cell malignancies

Nature Reviews Cancer volume 14, pages 219–232 (2014)Cite this article

Subjects

Key Points

  • Bruton's tyrosine kinase (BTK) was originally identified as a non-receptor protein tyrosine kinase that is defective in the inherited immunodeficiency disease X-linked agammaglobulinaemia (XLA).

  • BTK has long been known to be a key component of B cell receptor (BCR) signalling that regulates B cell proliferation and survival.

  • Recently, a small-molecule inhibitor of BTK, called ibrutinib, has shown antitumour activity in patients with various B cell malignancies.

  • The antitumour activity of BTK inhibition is not solely dependent on the role of BTK in BCR signalling.

  • BTK inhibition also targets Toll-like receptor (TLR) signalling, B cell adhesion and migration, as well as cells in the tumour microenvironment.

  • Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukaemia and mantle cell lymphoma leads to the effective expulsion of malignant B cells out of their nursing microenvironment.

  • For many different B cell malignancies, treatment with BTK inhibitors is expected to be more effective and have fewer toxic effects than currently used therapies.

Abstract

Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signalling and functions as an important regulator of cell proliferation and cell survival in various B cell malignancies. Small-molecule inhibitors of BTK have shown antitumour activity in animal models and, recently, in clinical studies. High response rates were reported in patients with chronic lymphocytic leukaemia and mantle cell lymphoma. Remarkably, BTK inhibitors have molecular effects that cannot be explained by the classic role of BTK in BCR signalling. In this Review, we highlight the importance of BTK in various signalling pathways in the context of its therapeutic inhibition.

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Figure 1: Structure of Bruton's tyrosine kinase and interactions.
Figure 2: Involvement of Bruton's tyrosine kinase in B cell receptor signalling.
Figure 3: Involvement of Bruton's tyrosine kinase in chemokine and Toll-like receptor signalling.

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Acknowledgements

Part of these studies were supported by the Association for International Cancer Research (to R.W.H.; 10–562) and the Dutch Arthritis Foundation (9-01-302).

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  1. Department of Pulmonary Medicine, Room Ee2251a, Erasmus MC Rotterdam, PO Box 2040, Rotterdam, NL 3000 CA, the Netherlands

    Rudi W. Hendriks, Saravanan Yuvaraj & Laurens P. Kil

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  1. Rudi W. Hendriks
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Glossary

B cell receptor

(BCR). An antigen receptor that is specifically expressed on the cell surface of B cells and composed of two immunoglobulin heavy (IgH) chains and two immunoglobulin light (IgL) chains.

Pre-BCR

A receptor that consists of an immunoglobulin heavy (IgH) chain, which is associated with two germline-encoded surrogate light chain components and is transiently expressed on the cell surface of pre-B cells after successful IgH chain rearrangement.

Diffuse large B cell lymphoma

(DLBCL). Numerous heterogeneous subtypes of mostly aggressive B cell lymphomas. The gene expression signatures of activated B cell-like DLBCL (ABC-DLBCL) and germinal centre-like DLBCL (GC-DLBCL) resemble those of activated peripheral blood B cells and germinal centre B cells, respectively.

Chronic lymphocytic leukaemia

(CLL). A leukaemia that mostly affects the elderly and that is characterized by a lymphocytosis (> 5 × 109 B cells per litre) of monoclonal CD5+ B cells.

Mantle cell lymphoma

(MCL). An aggressive form of non-Hodgkin's lymphoma that is characterized by cell cycle deregulation because of cyclin D1 overexpression, which is translocated as part of the t(11;14) translocation. Additional aberrations in genes that control the cell cycle and DNA damage responses have been reported.

Toll-like receptors

(TLRs). Innate receptors that are present on the cell surface or in endosomes and that recognize distinct, highly conserved molecular motifs, including polysaccharides, DNA and RNA, that are shared by pathogens.

SRC family kinases

SRC kinase, together with other members of the SRC kinase family, is a crucial regulator of cellular proliferation, survival and migration that is frequently activated in different types of cancers.

SRC homology domains

(SH domains). The SH domains SH2 and SH3 are protein modules that are involved in protein–protein interaction and that bind to phosphorylated tyrosines and proline-rich regions, respectively.

Pleckstrin homology domain

(PH domain). PH domains are protein modules that can bind to phosphatidylinositol lipids and that are involved in the recruitment of proteins to membranes — in particular, the cell membrane.

Wiskott–Aldrich syndrome protein

(WASP). The WASP protein is a cytoplasmic protein that is defective in the X-linked immunodeficiency Wiskott–Aldrich syndrome. It functions as an actin regulator by binding to and activating the ARP2–ARP3 complex.

Germinal centres

Structures found in the follicles of secondary lymphoid tissues that are composed of proliferating B cells that are induced to mutate antibody-encoding genes through somatic hypermutation after contact with antigen and T helper cells.

Follicular dendritic cells

(FDCs). Cells of mesenchymal origin that are found in B cell follicles of lymphoid tissues and that present antigen to B cells in immune complexes with antibodies binding to Fc receptors on their cell surface.

Interleukin-7 receptor signalling

(IL-7R signalling). The cytokine IL-7 is produced by bone marrow stromal cells and promotes proliferation and survival of B cell precursors in mice, but it does not seem to have a crucial role in human B cell development.

Pre-B cell acute lymphoblastic leukaemia

(Pre-B ALL). ALL is the most common childhood malignancy, derived from the precursor B cell compartment in the bone marrow.

Anergic response

A reversible programme that is characterized by low levels of B cell receptor (BCR) expression and limited BCR-induced activation of signalling molecules, which serves to silence autoreactive B cells.

Nurse-like cells

(NLCs). Peripheral blood monocyte-derived adherent cells to which chronic lymphocytic leukaemia (CLL) B cells become attached. This interaction can protect CLL cells from spontaneous apoptosis in vitro.

Waldenström's macroglobulinaemia

(WM). An uncommon B cell malignancy with heterogeneous clinical presentation that is characterized by high levels of monoclonal immunoglobulin M, secreted by lymphoplasmacytic lymphoma cells with bone marrow infiltration.

Multiple myeloma

(Also known as Kahler's disease). A malignancy of plasma cells that accumulate in the bone marrow. In contrast to resting healthy human plasma cells, multiple myeloma cells show a low rate of proliferation, which results from cell cycle deregulation.

Germinal centre B cell

An antigen-stimulated, proliferating B cell that is in contact with T helper cells and follicular dendritic cells in the microenvironment of lymphoid tissues.

Small lymphocytic lymphoma

(SLL). A different clinical manifestation of chronic lymphocytic leukaemia, in which most of the malignant cells are not in the bloodstream and bone marrow, but are in the lymph nodes and the spleen.

Follicular lymphoma

The most common type of indolent non-Hodgkin's lymphoma, which originates from germinal centre B cells. It is characterized by an overexpression of the anti-apoptotic BCL-2 protein, which is caused by translocation of the BCL2 gene near the site of the immunoglobulin heavy chain enhancer element.

Overall response rate

(ORR). The proportion of patients whose best overall response to a therapy is either complete or partial.

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Hendriks, R., Yuvaraj, S. & Kil, L. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer 14, 219–232 (2014). https://doi.org/10.1038/nrc3702

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