Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

Yu-Tzu Tai, Betty Y Chang, Sun-Young Kong, Mariateresa Fulciniti, Guang Yang, Yolanda Calle, Yiguo Hu, Jianhong Lin, Jian-Jun Zhao, Antonia Cagnetta, Michele Cea, Michael A Sellitto, Mike Y Zhong, Qiuju Wang, Chirag Acharya, Daniel R Carrasco, Joseph J Buggy, Laurence Elias, Steven P Treon, William MatsuiPaul Richardson, Nikhil C Munshi, Kenneth C Anderson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1877-87
Number of pages11
Issue number9
Publication statusPublished - 30 Aug 2012


  • Animals
  • Bone Marrow
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Chemokines
  • Coculture Techniques
  • Cytokines
  • Down-Regulation
  • Gene Expression
  • Humans
  • Immunoblotting
  • Mice
  • Mice, SCID
  • Multiple Myeloma
  • Osteoclasts
  • Osteolysis
  • Protein-Tyrosine Kinases
  • Pyrazoles
  • Pyrimidines
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stromal Cells
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays

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