title: FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell.
abstract: Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery.
authors.affiliation: The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China; Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, PR China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, PR China.
authors.forename: Peiqi
authors.initials: P
authors.lastname: Wang
authors.affiliation: The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jing
authors.affiliation: The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Yue
authors.affiliation: The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, PR China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China. Electronic address: li--jingyi@hotmail.com.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.affiliation: The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China.
authors.forename: Haixing
authors.initials: H
authors.lastname: Song
authors.affiliation: School of Pharmacy, Shihezi University, Shihezi 832003, PR China. Electronic address: liguoyulisa@163.com.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, PR China. Electronic address: liurui_scu@hotmail.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shihezi University, Shihezi 832003, PR China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D011743:Pyrimidines; D014508:Urea; C546842:MTOR protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C113399:PD 166866
keywords: Autophagy; Breast cancer; FGFR; PD166866; mTOR