Glioblastoma(GBM)is a malignant brain tumor that grows quickly,spreads widely,and is resistant to treatment.Fibroblast growth factor receptor(FGFR)1 is a receptor tyrosine kinase that regulates cellular processes,incl...Glioblastoma(GBM)is a malignant brain tumor that grows quickly,spreads widely,and is resistant to treatment.Fibroblast growth factor receptor(FGFR)1 is a receptor tyrosine kinase that regulates cellular processes,including proliferation,survival,migration,and dif-ferentiation.FGFR1 was predominantly expressed in GBM tissues,and FGFR1 expression was negatively correlated with overall survival.We rationally designed a novel small molecule CYY292,which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro.CYY292 also exerted an effect on the conserved Ser777 residue of FGFR1.CYY292 dose-depen-dently inhibited cell proliferation,epithelial-mesenchymal transition,stemness,invasion,and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells,and this effect was prevented by pharmacological inhibitors and critical gene knockdown.In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547.CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models.This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292,which targets FGFR1,on downstream signaling pathways directly reducing GBM cell growth,invasion,and metastasis and thus impairing the recruitment,activation,and function of immune cells.展开更多
Intrahepatic cholangiocarcinoma(iCCA)is a rare malignancy,constituting approximately 3-5%of hepatic tumors,with an increasing incidence in recent years(1).Early stage iCCA typically presents asymptomatically,often res...Intrahepatic cholangiocarcinoma(iCCA)is a rare malignancy,constituting approximately 3-5%of hepatic tumors,with an increasing incidence in recent years(1).Early stage iCCA typically presents asymptomatically,often resulting in its detection at advanced stages.Surgical resection remains the primary therapeutic approach for iCCA;however,a substantial proportion of patients are precluded from surgery due to disease progression,necessitating a reliance on pharmaceutical interventions(2).展开更多
基金supported by the National Natural Science Foundation of China(No.81971180,81973168 and 82003793)CAMS Innovation Fund for Medical Sciences(No.2019-12M-5-028)+1 种基金the Scientific Research Project of Wenzhou,Zhejiang,China(No.ZY2019001)the National Natural Science Foundation of Zhejiang Province,China(No.LZ22H300002).
文摘Glioblastoma(GBM)is a malignant brain tumor that grows quickly,spreads widely,and is resistant to treatment.Fibroblast growth factor receptor(FGFR)1 is a receptor tyrosine kinase that regulates cellular processes,including proliferation,survival,migration,and dif-ferentiation.FGFR1 was predominantly expressed in GBM tissues,and FGFR1 expression was negatively correlated with overall survival.We rationally designed a novel small molecule CYY292,which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro.CYY292 also exerted an effect on the conserved Ser777 residue of FGFR1.CYY292 dose-depen-dently inhibited cell proliferation,epithelial-mesenchymal transition,stemness,invasion,and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells,and this effect was prevented by pharmacological inhibitors and critical gene knockdown.In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547.CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models.This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292,which targets FGFR1,on downstream signaling pathways directly reducing GBM cell growth,invasion,and metastasis and thus impairing the recruitment,activation,and function of immune cells.
基金supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science(KAKENHI:21K07184)a grant from Smoking Research Foundation.
文摘Intrahepatic cholangiocarcinoma(iCCA)is a rare malignancy,constituting approximately 3-5%of hepatic tumors,with an increasing incidence in recent years(1).Early stage iCCA typically presents asymptomatically,often resulting in its detection at advanced stages.Surgical resection remains the primary therapeutic approach for iCCA;however,a substantial proportion of patients are precluded from surgery due to disease progression,necessitating a reliance on pharmaceutical interventions(2).
