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

• Published in: Blood 2012-08, Vol.120 (9), p.1877-1887
• Main Authors: 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., Zhong, Mike Y., Wang, Qiuju, Acharya, Chirag, Carrasco, Daniel R., Buggy, Joseph J., Elias, Laurence, Treon, Steven P., Matsui, William, Richardson, Paul, Munshi, Nikhil C., Anderson, Kenneth C.
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - 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; Hematologic and hematopoietic diseases; Humans; Immunoblotting; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Medical sciences; Mice; Mice, SCID; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteolysis - genetics; Osteolysis - metabolism; Osteolysis - prevention & control; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells - drug effects; Stromal Cells - metabolism; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays - methods
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-12-396853

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 = 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-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.