Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies

Abstract

Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.

Fig 1.

Ogden Bruton, MD. Photo with personalized autograph kindly provided by Billy F. Andrews, MD, Department of Pediatrics, University of Louisville, Louisville, KY.

Fig 2.

Milestones in Bruton's tyrosine kinase (BTK) research. CLL, chronic lymphocytic leukemia; FDA, US Food and Drug Administration; MCL, mantle-cell lymphoma; xid, X-linked immunodeficiency; XLA, X-linked agammaglobulinemia.

Fig 3.

Schematic domain structure of Bruton's tyrosine kinase (Btk). PH, Pleckstrin homology domain; TH, Tec homology domain; SH2 and SH3, Src homology domains.

Fig 4.

Role of Bruton's tyrosine kinase (BTK) in the B cell signaling. By signaling through the B-cell receptor (BCR), complex signaling cascades are initiated that recruit BTK to the cell membrane and activate other kinases, which leads to an increase in intracellular Ca2+ and activation of transcription κB (NF-κB). BTK also plays a role in chemokine receptor and adhesion molecule (integrin) signaling pathways and in signaling of multiple other surface receptors. BLNK, B-cell linker scaffold protein; GPCR, G protein-coupled receptor; PI3K, phosphoinositol-3 kinase; PIP, phosphatidylinositol; PLCγ2, phospholipase-C-γ2.