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 Matsui; Paul Richardson; Nikhil C Munshi; Kenneth C Anderson

doi:10.1182/blood-2011-12-396853

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 journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1877-87
Number of pages	11
Journal	Blood
Volume	120
Issue number	9
DOIs	https://doi.org/10.1182/blood-2011-12-396853
Publication status	Published - 30 Aug 2012

Keywords

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

Access to Document

10.1182/blood-2011-12-396853

Cite this

Tai, Y.-T., Chang, B. Y., Kong, S.-Y., Fulciniti, M., Yang, G., Calle, Y., Hu, Y., Lin, J., Zhao, J.-J., Cagnetta, A., Cea, M., Sellitto, M. A., Zhong, M. Y., Wang, Q., Acharya, C., Carrasco, D. R., Buggy, J. J., Elias, L., Treon, S. P., ... Anderson, K. C. (2012). Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood, 120(9), 1877-87. https://doi.org/10.1182/blood-2011-12-396853

@article{0ead4e06d5da4ea09d1a81d4c694863c,

title = "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.",

keywords = "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",

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

year = "2012",

month = aug,

day = "30",

doi = "10.1182/blood-2011-12-396853",

language = "English",

volume = "120",

pages = "1877--87",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "9",

}

Tai, Y-T, Chang, BY, Kong, S-Y, Fulciniti, M, Yang, G, Calle, Y, Hu, Y, Lin, J, Zhao, J-J, 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, KC 2012, 'Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma', Blood, vol. 120, no. 9, pp. 1877-87. https://doi.org/10.1182/blood-2011-12-396853

TY - JOUR

T1 - Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

AU - Tai, Yu-Tzu

AU - Chang, Betty Y

AU - Kong, Sun-Young

AU - Fulciniti, Mariateresa

AU - Yang, Guang

AU - Calle, Yolanda

AU - Hu, Yiguo

AU - Lin, Jianhong

AU - Zhao, Jian-Jun

AU - Cagnetta, Antonia

AU - Cea, Michele

AU - Sellitto, Michael A

AU - Zhong, Mike Y

AU - Wang, Qiuju

AU - Acharya, Chirag

AU - Carrasco, Daniel R

AU - Buggy, Joseph J

AU - Elias, Laurence

AU - Treon, Steven P

AU - Matsui, William

AU - Richardson, Paul

AU - Munshi, Nikhil C

AU - Anderson, Kenneth C

PY - 2012/8/30

Y1 - 2012/8/30

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Marrow

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cell Survival

KW - Chemokines

KW - Coculture Techniques

KW - Cytokines

KW - Down-Regulation

KW - Gene Expression

KW - Humans

KW - Immunoblotting

KW - Mice

KW - Mice, SCID

KW - Multiple Myeloma

KW - Osteoclasts

KW - Osteolysis

KW - Protein-Tyrosine Kinases

KW - Pyrazoles

KW - Pyrimidines

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Stromal Cells

KW - Tumor Microenvironment

KW - Xenograft Model Antitumor Assays

U2 - 10.1182/blood-2011-12-396853

DO - 10.1182/blood-2011-12-396853

M3 - Article

C2 - 22689860

SN - 0006-4971

VL - 120

SP - 1877

EP - 1887

JO - Blood

JF - Blood

IS - 9

ER -