Targeting B-Cell receptor signaling for anticancer therapy: the Bruton's tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies.

Ibrutinib (PCI-32765) is an orally active inhibitor of Bruton’s tyrosine kinase (BTK) that covalently binds to the cysteine Cys-481 of BTK and thereby irreversibly inactivates the kinase. In the report accompanying this article, the results of the first clinical study of ibrutinib in patients with relapsed/refractory B-cell malignancies are presented. Objective responses were observed in an impressive 60% of patients, including 16% complete responses, and adverse effects were minimal. This article provides an overview of the role of BTK for B-cell receptor (BCR) signaling and the importance of the BCR in B-cell malignancies. BTK is a cytoplasmic tyrosine kinase of the Tec family that is essential for BCR signaling. Loss-of-function BTK mutations cause X-linked agammaglobulinemia, which is characterized by the virtual absence of B cells and immunoglobulins and results in recurrent bacterial infections. BTK is expressed in B cells and myeloid cells but not in plasma cells or T lymphocytes. Moreover, its essential functions seem to be limited to B cells. BTK is required for BCR-induced calcium release, cell proliferation, and activation of the nuclear factor B (NFB) pathway. The BCR consists of a surface transmembrane immunoglobulin (Ig) receptor associated with the Ig (CD79A) and Ig (CD79B) chains. The BCR serves as the receptor for antigen and promotes cell growth, proliferation, and survival of normal and malignant B cells. On antigen binding, the tyrosine kinases LYN and SYK initiate a signal transduction cascade that involves several kinases, adapter molecules, and the generation of second messengers (Fig 1). Of the surface Ig isotypes, IgM is of particular importance for antigen-dependent signaling and is the isotype expressed by most mature B-cell malignancies. BCR signaling is increasingly implicated in the pathogenesis of some B-cell malignancies. Definitive experimental evidence comes from studies in the activated B-cell–like (ABC) subtype of diffuse large