Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies.
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.
All authors: The University of Texas MD Anderson Cancer Center, Houston, TX.
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All authors: The University of Texas MD Anderson Cancer Center, Houston, TX. jaburger@mdanderson.org.
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D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D040181:Genetic Diseases, X-Linked / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human