Dasatinib treatment results in a markedly diminished frequency of bone metastases after intracardiac injection of osteotropic MDA-MB-231 breast cancer cells in a xenograft mouse model

Aims: The development of skeletal breast cancer metastases depends on tumor cell Src-kinase activity. We were recently able to show that knockdown of TRAIL (TNF related apoptosis inducing ligand)-R2 in an osteotropic clone of MDA-MB-231 cells results in a diminished frequency of bone metastases by an impairment of homing mechanisms after intracardiac injection in a xenograft-mouse model. In vitro we also found a downregulation of Src kinase levels in these cells. We therefore aimed to examine a conceivably synergistic effect on the development of breast cancer bone metastases after treatment with Dasatinib, a tyrosine kinase inhibitor of Src family and Abl kinases, which has been shown to favor osteogenesis and inhibit growth of breast cancer metastases in patients.

Material and methods: MDA-MB-231 cells were treated with Dasatinib in vitro for functional analyses. In vivo, bone homing breast cancer cells were intracardially injected in mice (n = 30) and development of metastatic tumors was monitored by bioluminescence. Tumor associated bone loss was measured by µ-computed tomography. The treatment group (n = 15) received daily gavages of Dasatinib intraperitoneally.

Results: Surprisingly, we found a dose dependent induction of TRAIL-R2 expression after Dasatinib treatment in vitro. In vivo treatment of mice with Dasatinib resulted in a marked reduction of A) mice with metastases (- 34%) and B) mice with tibial metastases (-66%). Underlying mechanisms are now being explored.

Summary: Despite an overexpression of TRAIL-R2 in vitro treatment of mice with Dasatinib efficiently prevents skeletal metastasis after intracardiac injection of osteotropic MDA-MB-231 breast cancer cells.