Destructive bone lesions due to osteolytic bone disease (OBD) are a major cause of morbidity and mortality in multiple myeloma (MM) patients and the development of new therapeutic strategies is of great interest. In this study, we assessed the effect of SRC inhibition with saracatinib (AZD0530, AstraZeneca) on the development of MM and its associated OBD. We first determined SRC family kinase expression in the MM microenvironment and found that myeloma cells express SRC at low levels, which do not correlate with disease stage. SRC expression was found to increase during osteoclast differentiation and decrease during osteoblast differentiation. Next, we validated an inhibitory role of saracatinib on osteoclast differentiation and function. Saracatinib inhibited the differentiation and polarization of RAW264.7 and primary osteoclasts, reflected by a decrease of CTSK and DC-STAMP levels and a defective actin ring formation. This culminated in an inhibition of bone matrix resorption. In addition, saracatinib inhibited collagen secretion by MC3T3-E1 osteoblasts. In both the 5TGM.1 and 5T2MM murine myeloma models, bone destruction was markedly reduced following treatment with saracatinib, reflected by a restoration of multiple trabecular bone parameters to levels observed in healthy control mice, including BV/TV, Tb.N. and Tb.Th. These findings were corroborated by histomorphometric analyses. Although BM plasmocytosis was not affected in these mice, in vitro studies suggest synergism between bortezomib and saracatinib. In conclusion, we report a potent inhibitory preclinical effect of the SRC inhibitor saracatinib on the development of OBD in MM, further establishing SRC as a promising therapeutic target.
14 May 2016 - 17 May 2016