title: AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells.
abstract: Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings.
authors.affiliation: Department of Cancer Surgery, The First Affiliated Hospital of Bengbu Medical College, 287 Chang Huai Road, Bengbu, 233004, People's Republic of China, yaotingtingah163@163.com.
authors.forename: Ting-Jing
authors.initials: TJ
authors.lastname: Yao
authors.forename: Jin-Hai
authors.initials: JH
authors.lastname: Zhu
authors.forename: De-Feng
authors.initials: DF
authors.lastname: Peng
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cui
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Pei-hua
authors.initials: PH
authors.lastname: Lu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D063646:Carcinogenesis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C572463:AZD4547; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; D005346:Fibroblast Growth Factors; C546842:MTOR protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D058570:TOR Serine-Threonine Kinases