Abstract:
:Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17 nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5 nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.
journal_name
Bloodjournal_title
Bloodauthors
Tai YT,Chang BY,Kong SY,Fulciniti M,Yang G,Calle Y,Hu Y,Lin J,Zhao JJ,Cagnetta A,Cea M,Sellitto MA,Zhong MY,Wang Q,Acharya C,Carrasco DR,Buggy JJ,Elias L,Treon SP,Matsui W,Richardson P,Munshi NC,Anderson KCdoi
10.1182/blood-2011-12-396853subject
Has Abstractpub_date
2012-08-30 00:00:00pages
1877-87issue
9eissn
0006-4971issn
1528-0020pii
blood-2011-12-396853journal_volume
120pub_type
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