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

Roy Heusschen1, Joséphine Muller1, Marilène Binsfeld1

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

Oncotarget
|April 21, 2016
PubMed

Insights

Saracatinib, a SRC inhibitor, effectively reduces bone loss in multiple myeloma (MM) models by inhibiting osteoclast activity. This study highlights SRC inhibition as a promising therapeutic strategy for MM-associated osteolytic bone disease.

Area of Science:

  • Oncology
  • Bone Biology
  • Pharmacology

Background:

  • Multiple myeloma (MM)-associated osteolytic bone disease significantly impacts patient morbidity and mortality.
  • The proto-oncogene SRC is implicated in MM pathogenesis and represents a potential therapeutic target.
  • Developing novel therapeutic strategies for MM-related bone complications is crucial.

Purpose of the Study:

  • To investigate the therapeutic potential of the SRC inhibitor saracatinib (AZD0530) in multiple myeloma (MM) and its associated osteolytic bone disease.
  • To evaluate the effects of saracatinib on osteoclast and osteoblast differentiation and function in vitro.
  • To assess the impact of saracatinib on MM tumor burden and bone loss in preclinical MM models.

Main Methods:

  • In vitro studies assessed saracatinib's effects on osteoclast differentiation, polarization, and resorptive function, and on osteoblast collagen deposition and matrix mineralization.
  • In vivo studies utilized 5TGM.1 and 5T2MM murine MM models to evaluate saracatinib's impact on MM cell proliferation, tumor burden, and bone loss.
  • Histomorphometric analyses were performed to elucidate the mechanisms underlying bone changes.

Main Results:

  • Saracatinib demonstrated inhibitory effects on osteoclast differentiation and function in vitro.
  • In osteoblasts, saracatinib affected collagen deposition and matrix mineralization.
  • Saracatinib treatment led to a significant reduction in bone loss in MM-bearing mice, restoring trabecular bone parameters.
  • No significant impact on MM cell proliferation or tumor burden was observed with saracatinib monotherapy.

Conclusions:

  • SRC inhibition with saracatinib effectively mitigates osteolytic bone disease in preclinical MM models.
  • The therapeutic benefit appears to be primarily through the inhibition of bone resorption.
  • SRC inhibition represents a promising strategy for managing multiple myeloma-associated osteolytic bone disease.
Keywords:
c-SRCmultiple myelomaosteoclastosteolytic bone diseasesaracatinib

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