Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon

Abstract

FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1–3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples.

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

“…In order to investigate whether the induction of oxidative stress by FGF/FGFR inhibition is a mechanism specific for FGF-dependent lung cancers, we tested the effect of NSC12 on two other human lung cancer cell lines: FGF-dependent H520 cells and FGF-independent HCC827 cells. H520 cells, like H1581 cells, are characterized by FGFR1 amplification and autocrine FGF stimulation ( Table S1 ) [ 19 ], whereas HCC827 cells are adenocarcinoma cells that harbor a tumor driving mutation in the TK domain of EGFR which makes these cells independent from the FGF/FGFR system, notwithstanding their FGF/FGFR expression ( Table S1 ) [ 25 ]. As previously reported [ 21 ], NSC12 significantly reduced the proliferation of FGF-dependent H520 cells, but not of FGF-independent HCC827 cells ( Figure 3 A).…”

“…This promotes cancer cell survival, chemotherapy resistance and growth of lung tumor cell lines [ 14 , 17 ]. Accordingly, lung cancer cell lines (like NCI-H1581 and NCI-H520 cells) have been identified that harbor amplification of FGFR1 and are highly sensitive to FGFR inhibitors in vitro and in vivo [ 18 , 19 ].…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…Gene amplification Amplification of FGFR is reported to be present in 66% of cancers with an FGFRs alteration, with FGFR1 amplification being the most common (42%) (Helsten et al, 2015). Approximately 20% of the squamous cell carcinomas (SCC) of the lung present with FGFR1 amplification and this has been shown to be associated with smoking in a dose-dependent fashion (Rooney et al, 2016). Recently a meta-analysis showed that patients with FGFR gene amplification have a worse prognosis than FGFR wild-type patients.…”

The association between fibroblast growth factor receptor 1 gene amplification and lung cancer: a meta-analysis

“…Fibroblast growth factor receptor 1 (FGFR1) is an emerging molecular target for the treatment of SCC of the lung [9][10][11], and several clinical trials of FGFR inhibitors in NSCLC are currently underway [12][13][14]. Amplification of the FGFR gene has been found in epithelial malignancies, such as gastric, breast, oral squamous cell, ovarian, and bladder carcinomas [15,16], and more recently, in lung SCC.…”