title: Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors.
abstract: The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.
authors.affiliation: Molecular Pathology Lab, Massachusetts General Hospital Cancer Center, Boston, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dienstmann
authors.affiliation: Medical Oncology Department.
authors.forename: J
authors.initials: J
authors.lastname: Rodon
authors.affiliation: Medical Oncology Department; Translational Genomics Lab.
authors.forename: A
authors.initials: A
authors.lastname: Prat
authors.affiliation: Medical Oncology Department.
authors.forename: J
authors.initials: J
authors.lastname: Perez-Garcia
authors.affiliation: Medical Oncology Department.
authors.forename: B
authors.initials: B
authors.lastname: Adamo
authors.affiliation: Medical Oncology Department.
authors.forename: E
authors.initials: E
authors.lastname: Felip
authors.affiliation: Medical Oncology Department.
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Molecular Pathology Lab, Massachusetts General Hospital Cancer Center, Boston, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Molecular Oncology Lab, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Medical Oncology Department. Electronic address: jtabernero@vhebron.net.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D051518:Fibroblast Growth Factor 3 / Q000235:genetics; D005784:Gene Amplification; D006801:Humans; D054559:Hyperphosphatemia / Q000628:therapy; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; C496371:FGFR4 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: amplification; cancer; fibroblast growth factor receptor FGFR; hyperphosphatemia; oncogene; targeted therapy