1. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma.
- Author
-
Tai, Yu-Tzu, Chang, Betty Y., Kong, Sun-Young, Fulciniti, Mariateresa, Yang, Guang, Calle, Yolanda, Hu, Yiguo, Lin, Jianhong, Zhao, Jian-Jun, Cagnetta, Antonia, Cea, Michele, Sellitto, Michael A., Zheng, Mike Y., Wang, Qiuju, Acharya, Chirag, Carrasco, Daniel R., Buggy, Joseph J., Elias, Laurence, Treon, Steven P., and Matsui, William
- Subjects
- *
PROTEIN-tyrosine kinases , *BONE marrow , *MULTIPLE myeloma treatment , *THERAPEUTICS , *CYTOKINES , *CHEMOKINES - Abstract
Bruton tyrosine kinase (Btk) has a welldefined 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-&ggr;2 In OCs, resulting In diminished TRAP5b ((ED50 = 17nM) 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 = 0.5nM) and MM patients. It decreased SDF-1-Induced migration of MM cells, and down-regulated MIP1-&agr;/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. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF