Abstract
The insulin growth factor-I receptor (IGF1R) signaling is a key mechanism for osteosarcoma (OS) cell proliferation. GSK1904529A is a novel small molecule IGF1R kinase inhibitor. Its activity against OS cells was tested. In both established OS cell lines (Saos-2 and MG-63) and primary human OS cells, treatment with GSK1904529A (at nM concentrations) significantly inhibited cell proliferation. At the molecular level, GSK1904529A almost completely blocked IGF1R activation in OS cells, and inhibited downstream AKT-ERK activation. IGF1R silence by targeted shRNA also inhibited AKT-ERK activation and Saos-2 cell proliferation. Significantly, GSK1904529A was unable to further inhibit proliferation of IGF1R-silenced Saos-2 cells. In vivo, GSK1904529A administration orally inhibited Saos-2 tumor growth in nude mice. Together, these results suggest that targeting IGF1R by GSK1904529A inhibits OS cell growth in vitro and in vivo.
Highlights
Over the past decades, the prognosis of osteosarcoma (OS) has been improved [1,2,3,4,5]
GSK1904529A administration orally inhibited Saos-2 tumor growth in nude mice. These results suggest that targeting IGF1R by GSK1904529A inhibits OS cell growth in vitro and in vivo
Over-expression and/or hyper-activation of IGF1R tyrosine kinase will lead to constitutive activation of downstream signalings, including the insulin receptor substrate-1 (IRS-1) as well as AKT-ERK cascade [14, 15], which are important for a number cancerous behaviors, including cell proliferation and survival [11,12,13]
Summary
The prognosis of osteosarcoma (OS) has been improved [1,2,3,4,5]. The fiveyear overall survival of OS has yet reached a plateau [1,2,3,4,5]. A better understanding of molecular pathology could likely lead to further improvements of OS treatment [8,9,10]. The insulin growth factor-I (IGF-I)/IGF-I receptor (IGF1R) pathway has been considered as an important contributor for OS tumorigenesis and progression [11,12,13]. Over-expression and/or hyper-activation of IGF1R tyrosine kinase will lead to constitutive activation of downstream signalings, including the insulin receptor substrate-1
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