Abstract
Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine–cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met and FGFR pathways may have synergistic clinical benefits when targeting FGFR-dependent LC.
Highlights
Lung cancer (LC) is the leading cause of cancer-related mortality worldwide.[1]
The full panel of LC cell lines, ranked from the most to the least sensitive to AZD4547 and BAY1163877 based on inhibition of cell proliferation, with the information of FGFR1 gene copy number and mRNA expression is shown in Supplementary Table 1
We evaluated in vitro antitumor activity and pharmacodynamic effects of selective fibroblast growth factor receptor (FGFR)-tyrosine kinase inhibitors (TKIs) in a panel of LC
Summary
Lung cancer (LC) is the leading cause of cancer-related mortality worldwide.[1]. Recently, there has been considerable advances of molecularly-targeted therapies in LC patients; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib and afatinib, are utilized in patients with EGFR mutations, while the anaplastic lymphoma kinase (ALK) inhibitor, crizotinib, is employed in those with ALK rearrangement.[2]. Our groups and others have already reported FGFR1 amplification in squamous cell carcinoma, a major histologic subtype of LC, at a frequency of 13–22%.3–6. Fibroblast growth factors receptor (FGFR) gene amplification and overexpression is a common alteration and a potential drug target in LC.[7] Aberrant FGF signaling can promote tumor development by directly driving cancer cell survival, motility, invasiveness, proliferation, epithelial-to-mesenchymal transition (EMT) and angiogenesis.[8] Activation of FGF signaling leads to phosphorylation of the bound fibroblast growth factor receptor substrate 2 (FRS2) and downstream activation of Ras/Raf/MAPK (mitogen-activated protein kinase), phosphoinositide 3-kinase (PI3K)/AKT and Janus kinase/signal transducer and activator of transcription (STAT) pathways.[9]
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