SRC kinase inhibition with saracatinib limits the development of osteolytic bone disease in multiple myeloma.
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.
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.
Roy
R
Heusschen
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.
Joséphine
J
Muller
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.
Marilène
M
Binsfeld
INSERM-UMR-1132, Hôpital Lariboisière and Université Paris Diderot, Paris, France.
Caroline
C
Marty
Department of Chemical Engineering, PEPs (Products, Environments, Processes), University of Liège, Liège, Belgium.
Erwan
E
Plougonven
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.
Sophie
S
Dubois
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.
Nadia
N
Mahli
Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
Karen
K
Moermans
Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
Geert
G
Carmeliet
Department of Chemical Engineering, PEPs (Products, Environments, Processes), University of Liège, Liège, Belgium.
Angélique
A
Léonard
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.|Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium.
Frédéric
F
Baron
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.|Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium.
Yves
Y
Beguin
Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
Eline
E
Menu
INSERM-UMR-1132, Hôpital Lariboisière and Université Paris Diderot, Paris, France.
Martine
M
Cohen-Solal
Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.|Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium.
Jo
J
Caers
D000284:Administration, Oral; D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000187:drug effects*; D011799:Quinazolines / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D052117:Benzodioxoles; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases
c-SRC; multiple myeloma; osteoclast; osteolytic bone disease; saracatinib