Oncotarget

Research Papers:

SRC kinase inhibition with saracatinib limits the development of osteolytic bone disease in multiple myeloma

Roy Heusschen _, Joséphine Muller, Marilène Binsfeld, Caroline Marty, Erwan Plougonven, Sophie Dubois, Nadia Mahli, Karen Moermans, Geert Carmeliet, Angélique Léonard, Frédéric Baron, Yves Beguin, Eline Menu, Martine Cohen-Solal and Jo Caers

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Oncotarget. 2016; 7:30712-30729. https://doi.org/10.18632/oncotarget.8750

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Abstract

Roy Heusschen1,*, Joséphine Muller1,*, Marilène Binsfeld1, Caroline Marty3, Erwan Plougonven4, Sophie Dubois1, Nadia Mahli1, Karen Moermans5, Geert Carmeliet5, Angélique Léonard4, Frédéric Baron1,2, Yves Beguin1,2, Eline Menu6, Martine Cohen-Solal3, Jo Caers1,2

1Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium

2Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium

3INSERM-UMR-1132, Hôpital Lariboisière and Université Paris Diderot, Paris, France

4Department of Chemical Engineering, PEPs (Products, Environments, Processes), University of Liège, Liège, Belgium

5Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium

6Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium

*These authors have contributed equally to this work

Correspondence to:

Jo Caers, email: [email protected]

Keywords: multiple myeloma, osteolytic bone disease, c-SRC, saracatinib, osteoclast, AZD0530, cancer

Received: September 25, 2015    Accepted: March 31, 2016    Published: April 15, 2016

ABSTRACT

Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest. The proto-oncogene SRC is an attractive target for such a strategy. In the current study, we investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models. In vitro data showed an inhibitory effect of saracatinib on osteoclast differentiation, polarization and resorptive function. In osteoblasts, collagen deposition and matrix mineralization were affected by saracatinib. MM cell proliferation and tumor burden remained unaltered following saracatinib treatment and we could not detect any synergistic effects with drugs that are part of standard care in MM. We observed a marked reduction of bone loss after treatment of MM-bearing mice with saracatinib as reflected by a restoration of trabecular bone parameters to levels observed in naive control mice. Histomorphometric analyses support that this occurs through an inhibition of bone resorption. In conclusion, these data further establish SRC inhibition as a promising therapeutic approach for the treatment of MM-associated osteolytic bone disease.


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