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  • br Molecular aberrations in the FGFR signaling pathway br

    2021-09-15


    Molecular aberrations in the FGFR signaling pathway
    Non–small cell lung cancer
    Small cell lung cancer Integrated methosulfate synthesis analysis revealed focal amplification of FGFR1 in 6% of SCLC cases. In another study with PD173074, Pardo et al. used two human SCLC xenograft models, H-510 and H-69, and demonstrated decreased proliferation in a dose-dependent manner when the drug was administered orally for 28 days. Longer median survival was observed in the H-150 xenograft than in the control animals, with the effect of cisplatin being potentiated by concurrent use of PD173074. In addition, complete remission was observed in half the mice for longer than 6 months. Voortman et al. reported high–copy number gains of the FGFR1 gene in SCLC. The frequency of 33.3%, suggests that this could be a possible therapeutic target. Yet another study of 13 SCLC cell lines and 68 SCLC tumor samples from patients reported that FGFR1 mutations and focal amplifications were rare in SCLC (focal amplification of the FGFR1 gene was present in only five tumor samples with high-level focal amplification in only one tumor sample). A recent study reported a subset of patients with SCLC with an activated FGFR pathway that was evidenced by positive FGF2, FGF9, and FGFR1 protein or FGFR1 gene copy number. Further studies are warranted to test the benefit of FGFR inhibitors in this population of patients with SCLC. There are no approved targeted therapies in SCLC. This lack of approved therapies is due partly to the scarcity of tissue for molecular studies because of the difficulty in obtaining tissue samples on account of the aggressive nature of the disease process. Multiple phase 1 and phase 2 studies of the effect of FGFR inhibitors on patients with SCLC do exist, however (Tables 2 and 3).
    Clinical development of FGFR inhibitors in lung cancer The first class of agents to be studied as FGFR inhibitors were multikinase antiangiogenic compounds that had initially been developed to target vascular endothelial growth factor receptor (VEGFR). With the emergence of FGFR as an important target for cancer therapy, however, these agents were repositioned as FGFR inhibitors and studied for their FGFR-inhibitory activity. These agents include brevanib, cediranib, dovitinib, lucitanib, and nintedanib. In the past few years, however, a number of potent and specific second-generation inhibitors of FGFR have been introduced into the clinic. These second-generation inhibitors are listed in Table 2.
    Conclusions The FGFR pathway is crucial to normal cellular functioning. Dysregulation in this pathway has been identified in NSCLC, particularly squamous cell lung cancer. A number of FGFR inhibitors are being evaluated in NSCLC. Unfortunately, as described earlier, clinical activity to date has been modest at best. In the current era, agents inhibiting protein targets of genetic derangements that drive lung cancer growth, such as EGFR tyrosine kinase inhibitors and ALK and ROS inhibitors, yield response rates in excess of 40%. Thus, the low-level responses seen with the aforementioned FGFR inhibitors have been considered disappointing. Several potential reasons underlying this low activity exist. First, the frequency of activating mutations in the FGFR gene in NSCLC is extremely low. Second, most studies have selected tumors with amplification of the FGFR gene, but the definition of gene amplification in clinical trials has not been uniform. Gene amplification is the production of multiple copies of a particular gene, which then amplify the phenotype attributed to the gene. Gene copy number can also be increased in cases of polysomy, which is distinguished by an increase in copy number of all genes on the polysomic chromosome and is therefore not a selective phenomenon. Unlike mutations that are dichotomized molecular events—cells are mutated or not—the level of gene amplification can vary. It is quite likely that the cell’s degree of “addiction” to a gene may be proportional to the number of excess copies. In support of this idea, a recent report by Gadgeel et al. demonstrated that a 3.5-fold amplification of FGFR was of clinical significance. Interestingly, in their series the rates of FGFR1 amplification using the cutoff level of 3.5 were 5.1% in squamous cell and 4.1% in adenocarcinoma. Thus, future studies may have to either use a higher cutoff for defining FGFR amplification, or stratify patients into “low,” “moderate,” and “high” amplification groups to better discern the efficacy of these compounds.