Anti-cancer Effect And Mechanism Of GZD856 As A Novel Small Molecular PDGFR Inhibitor Against Lung Cancer In Vitro And In Vivo

Platelet-derived growth factor receptors(PDGFRα/β) play critical roles in the autocrine-stimulated growth and recruitment of cancer-associated fibroblasts(CAFs) of human lung cancer cells. In this research, we investigated the therapeutic effect and mechanism of GZD856 as a novel small molecular PDGFR inhibitor against lung cancer.We firstly investigated the kinase inhibitory and anti-proliferation activities of GZD856 in vitro through ELISA and MTT method respectivly. We also evaluated the effets of GZD856 on cell cycle and apoptosis by Flow cytometry. Then we studied anticancer efficacies of GZD856 in xenograft and orthotopic models. At last, we elucidated the antitumor mechanisms of GZD856 by Western blot and immunohistochemistry(IHC) assays.We have identified GZD856 as a new PDGFR inhibitor through different experiment technologis which potently inhibited PDGFRα/β kinase activity and blocks the signaling pathway both in vitro and in vivo. It strongly suppresses the proliferation of PDGFRα amplified H1703(PDGFRβ-) human lung cancer cells and demonstrates significant in vivo antitumor efficacy in a xenograft mouse model. Although GZD856 only displays limited in vitro anti-proliferative efficiency against PDGFRα-/PDGFRβ+ A549 lung cancer cells, it efficiently inhibits the in vivo growth and metastasis events of A549 cancer cells in the xenograft and orthotopic models, respectively. The promising in vivo antitumor activity of GZD856 in A549 models may result from its suppression on PDGFR-related microenvironment factors, such as recruitment of CAFs and collagen content in the stromal cells. GZD856 exhibits a long half-life of 22.2 hr, optimal plasma exposure(Cmax, 899.5 μg/L) and a good oral bioavailability of 78% in rats. And its LD50 value in ICR mice is about 497.0 mg/kg(po).In conclusion, GZD856 was idenfited as a novel PDGFRα/β inhibitor, which may be considered as a new promising candidate for anti-lung cancer drug development.