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  • Compared to a large database of


    Compared to a large database of NSCLC samples matched for disease type, many of the frequently altered genes were similar to those seen in this series of FGFR fusion-positive samples; however, there were notable exceptions. As expected, alterations in known NSCLC drivers (KRAS and EGFR) were significantly less common in this series than in FGFR wild-type NSCLC. STK11 alterations were also significantly less common in this series. Notably, amplification of genes encoding the FGFR ligands FGF3, FGF4, and FGF19 and FRS2 was significantly more common in FGFR fusion–positive cases than in FGFR wild-type NSCLC. In conclusion, FGFR3-TACC3 fusions, as well as diverse FGFR1, FGFR2, FGFR3, and FGFR4 fusions retaining m6A the FGFR kinase domain likely representing targetable drivers, were found in 0.2% of NSCLCs in this study. Unlike other classic driver fusions in NSCLC, which most commonly occur in adenocarcinomas, 40% of FGFR fusion–positive cases in our data set were SCCs. CGP to detect these alterations as part of routine clinical care, as well as continued clinical development of effective FGFR inhibitors in NSCLC, is warranted.
    Methods A systematic analysis of the literature was conducted on March 15, 2015, by performing a MeSH (medical subject headings) search in PubMed using the terms FGFR and FGF combined with NSCLC, squamous cell lung cancer, and therapeutics. The search was limited to English-language articles published between January 1, 1990, and March 15, 2015. Abstracts from the annual meetings of the American Society of Clinical Oncology, European Society of Medical Oncology, and American Association for Cancer Research and the AACR-NCI-EORTC (American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer) International Conference on Molecular Targets and Cancer Therapeutics published between January 1, 2000, and March 15, 2015, were also considered for inclusion. The references lists of the articles identified were also searched for other relevant articles.
    Introduction The m6A growth factor receptor (FGFR) pathway plays a key role in signal transduction in lung cancer. It controls cellular processes such as cell cycle progression, migration, metabolism, survival, proliferation, and differentiation. It also activates multiple signal transduction pathways, including Rat Sarcoma (RAS) kinase and mitogen-activated protein kinase (MAPK), which in addition to performing other proliferative functions, are also involved in the formation of new blood vessels. Thus, FGFR is central to angiogenesis, embryogenesis, inflammation, and malignant tumor cell proliferation.
    FGFR signaling FGFR signaling is achieved by changes in receptor conformation upon ligand binding, thus leading to receptor dimerization and subsequent activation by autophosphorylation of the tyrosine kinase intracellular domains (see Fig. 1). FGFs require heparin sulfate proteoglycans to activate FGFR. The receptor dimer is stabilized by a secondary binding site involving interactions between FGF and Ig2 of the second receptor in the complex, as well as by receptor–receptor interactions. Heparin or heparin sulfate proteoglycans are also necessary for stable dimerization of the FGF–FGFR complexes. As shown in Figure 2, the activated FGFR phosphorylates FRS2 on several sites, thereby allowing the recruitment of the adaptor proteins, son of sevenless, and growth factor receptor–bound protein 2 (GRB2) to activate RAS and the downstream RAF and MAPK pathways. The activated MAPK pathway is necessary for cell cycle progression. Further downstream signaling occurs by means of two main pathways through the intracellular receptor, FRS2 and phospholipase Cg, thus ultimately leading to up-regulation of the RAS-dependent MAPK and RAS-independent phosphoinositide 3-kinase–AKT signaling pathways. After phospholipase Cg is activated, it hydrolyzes phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate and diacylglycerol, thereby activating protein kinase C, which partly reinforces activation of the MAPK pathway by phosphorylating RAF. Several other pathways are also activated by FGFRs depending on the cellular context, including the p38 MAPK and Jun N-terminal kinase pathways, signal transducer and activator of transcription signaling,19, 20 and ribosomal protein S6 kinase 2.