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.
Highlights
Lung cancer represents the leading cause of cancer-related deaths [1] and remains one of the most challenging diseases to treat
Several therapeutic targets were identified as altered in squamous Non-small cell lung cancer (NSCLC) through mutation or amplification including FGFR1 amplifications which that been identified in ~20% of sqNSCLC cases [6, 7]
The gene expression data presented here suggests the presence of a broad amplicon in the region of FGFR1 on chromosome 8. We further explored this amplicon through in-depth high resolution genomic analysis of the FGFR1 locus using a custom CGH array in a subset of five sqNSCLC tissues, four of which carried FGFR1 amplification by FISH (S2 Table)
Summary
Lung cancer represents the leading cause of cancer-related deaths [1] and remains one of the most challenging diseases to treat. Non-small cell lung cancer (NSCLC) is subdivided into histological subtypes, adenocarcinoma, large cell carcinoma and squamous cell carcinoma and together these represent about 85% of lung cancer cases. EGFR inhibitors are approved for EGFR mutation positive tumours and anaplastic lymphoma kinase inhibitors are approved for EML4-ALK fusion positive tumours [2,3,4]. These genetic events are limited to the adenocarcinoma subtype and until the recent approval of the immunotherapy nivolumab for PD-L1 positive cancers no targeted therapies were approved in the squamous subtype to date [5]. Several therapeutic targets were identified as altered in squamous NSCLC (sqNSCLC) through mutation or amplification including FGFR1 amplifications which that been identified in ~20% of sqNSCLC cases [6, 7]
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