title: Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1.
abstract: Lung cancer is still the leading cause of cancer-related deaths worldwide. Identifying new oncogenic drivers and developing efficient inhibitors through molecular targeting approaches are crucial for improving therapies. The aim of this study was to investigate whether targeting fibroblast growth factor receptor 1 (FGFR1) with ponatinib inhibits the cell growth in both established and primary lung cancer cells overexpressing FGFR1. Eighty-eight non-small cell lung cancer (NSCLC) and paired normal tissue specimens were analyzed by real-time RT-PCR for FGFR1 gene expression. We identified four cell lines and two newly established primary lung cancer cultures that showed high FGFR1 expression levels, and evaluated the effect of the novel FGFR1 inhibitor ponatinib on cell growth. Approximately 50% (30 out of 59) NSCLC specimens expressed FGFR1>2-fold compared with their adjacent normal counterparts using quantitative RT-PCR. Ponatinib treatment of established NSCLC cell lines expressing higher levels of FGFR1 resulted in marked cell growth inhibition and suppression of clonogenicity. This growth inhibition was associated with inactivation of FGFR1 and its downstream targets. FGFR1 knockdown by shRNA achieved similar results when compared to treatment with ponatinib. Furthermore, ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1.
authors.affiliation: Cancer Center, Department of Medicine, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Ren
authors.forename: Mei
authors.initials: M
authors.lastname: Hong
authors.forename: Gentao
authors.initials: G
authors.lastname: Liu
authors.forename: Hongjin
authors.initials: H
authors.lastname: Wang
authors.forename: Vijay
authors.initials: V
authors.lastname: Patel
authors.forename: Paul
authors.initials: P
authors.lastname: Biddinger
authors.forename: Jeane
authors.initials: J
authors.lastname: Silva
authors.forename: John
authors.initials: J
authors.lastname: Cowell
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Hao
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1