Targeting the fibroblast growth factor receptor family in cancer.
Fibroblast growth factors (FGFs) regulate a plethora of biological functions, in both the embryonic and adult stages of development, binding their cognate receptors and thus activating a variety of downstream signalling pathways. Deregulation of the FGF/FGFR signalling axis, observed in multifarious tumor types including squamous non-small cell lung cancer, occurs through genomic FGFR alterations that drive ligand-independent receptor signalling or alterations that support ligand-dependent activation. Mutations are not restricted to the tyrosine kinase domain and aberrations appear to be tumor type dependent. As well as its complementarity and synergy with VEGF of particular interest is the interplay between FGFR and EGFR and the ability of these pathways to offer a compensatory signalling escape mechanism when either is inhibited. Hence there exists a rationale for a combinatorial approach to inhibition of these dysregulated pathways to reverse drug resistance. To date, several multi-target tyrosine kinase inhibitors as well as FGFR specific tyrosine kinase inhibitors (TKIs), monoclonal antibodies and FGF ligand traps have been developed. Promising preclinical data has resulted in several drugs entering clinical trials. This review explores aberrant FGFR and its potential as a therapeutic target in solid tumors.
Thoracic Oncology Research Group, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland.
Niamh
N
Hallinan
Thoracic Oncology Research Group, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland.
Stephen
S
Finn
Thoracic Oncology Research Group, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland.
Sinead
S
Cuffe
Thoracic Oncology Research Group, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland.
Shereen
S
Rafee
Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Australia.
Kenneth
K
O'Byrne
Thoracic Oncology Research Group, Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland.
Kathy
K
Gately
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors
EGFR; FGF ligand; FGFR; Receptor tyrosine kinase; Targeted therapy