Abstract:
:Bruton agammaglobulinemia tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, is a component of the B-cell receptor signaling pathway. Ibrutinib, a BTK inhibitor, has demonstrated a significant clinical activity against chronic lymphocytic leukemia (CLL) in early clinical trials. Understanding the molecular mechanisms of action would shed light on CLL pathophysiology and provide additional opportunities for the development of new therapies. In this study, we have chosen an in vivo approach by employing an ongoing phase 1b trial of ibrutinib. We prospectively collected and analyzed serial samples from the CLL patients before and after the initiation of ibrutinib. We found that the blockage of cell proliferation was one of the primary effects of ibrutinib against leukemic CLL cells in vivo. Using a co-culture system that induces CLL proliferation in vitro, analysis of several parameters, including Ki-67 expression and bromodeoxyuridine (BrdU) incorporation, revealed that the proliferation of CLL cells was directly inhibited by ibrutinib. Furthermore, activities of BTK and phospholipase Cγ2 as well as downstream signaling molecules, AKT and ERK, were all coordinately downregulated over time in ibrutinib-treated patients. Our findings suggest that the cell proliferation is one of the essential properties of CLL. Blocking cell proliferation via inhibition of BTK-mediated signaling may contribute to clinical responses in ibrutinib-treated patients.
journal_name
Leukemiajournal_title
Leukemiaauthors
Cheng S,Ma J,Guo A,Lu P,Leonard JP,Coleman M,Liu M,Buggy JJ,Furman RR,Wang YLdoi
10.1038/leu.2013.358subject
Has Abstractpub_date
2014-03-01 00:00:00pages
649-57issue
3eissn
0887-6924issn
1476-5551pii
leu2013358journal_volume
28pub_type
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