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

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.

• Authors: 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 Matsui, Paul Richardson, Nikhil C Munshi, Kenneth C Anderson
• Journal: Blood (Blood) Vol. 120 Issue 9 Pg. 1877-87 (Aug 30 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22689860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Cytokines
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• Btk protein, mouse
• Adenine

Topics

• Adenine (analogs & derivatives)
• Agammaglobulinaemia Tyrosine Kinase
• Animals
• Bone Marrow (drug effects, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chemokines (metabolism)
• Coculture Techniques
• Cytokines (metabolism)
• Down-Regulation (drug effects)
• Gene Expression (drug effects)
• Humans
• Immunoblotting
• Mice
• Mice, SCID
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Osteoclasts (drug effects, metabolism)
• Osteolysis (genetics, metabolism, prevention & control)
• Piperidines
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Stromal Cells (drug effects, metabolism)
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays (methods)