Department of Medicine, Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO; Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Medicine, Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO.
Clin Lung Cancer. 2018 Sep;19(5):450-456. doi: 10.1016/j.cllc.2018.06.004. Epub 2018 Jun 28.
To test whether a microRNA (miRNA) panel may serve as an alternative biomarker of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor sensitivity in lung cancer.
Histologically diverse lung cancer cell lines were submitted to assays for ponatinib and AZD4547 sensitivity. miRNAs, FGFR1 messenger RNA, gene copy number, and protein expression were detected by real-time quantitative PCR, fluorescence in-situ hybridization, and immunoblotting in 34 lung cancer cell lines.
Among 34 cell lines, 14 exhibited ponatinib sensitivity and 20 exhibited AZD4547 sensitivity (drug concentration causing 50% inhibition values < 100 nmol/L). A total of 39 of the 377-miRNA set were initially identified from the 4 paired ponatinib-sensitive or -insensitive cell lines to have at least an 8-fold differential expression and then were detected in all the 34 cell lines. A predictive panel of 3 miRNAs (let-7c, miRNA155, and miRNA218) was developed that had an area under the curve (AUC) of 0.886 with a sensitivity of 71.4% and specificity of 77.3% to predict response to ponatinib. The miRNA panel performed similar to FGFR1 protein expression (AUC = 0.864) and messenger RNA expression (AUC = 0.939), and better than FGFR1 amplification (AUC = 0.696). Furthermore, we validated this panel using data for sensitivity to AZD4547 in the cell line cohort with an AUC of 0.931 and a sensitivity of 73.3% and specificity of 76.2%, respectively.
The developed miRNA panel (let-7c, miRNA155, and miRNA218) may be useful in predicting response to FGFR tyrosine kinase inhibitors, either ponatinib or AZD4547 in lung cancer cell lines, and warrants further validation in the clinical setting.
检测 miRNA -panel 是否可以作为成纤维细胞生长因子受体（FGFR）酪氨酸激酶抑制剂在肺癌中敏感性的替代生物标志物。
将组织学多样化的肺癌细胞系进行 ponatinib 和 AZD4547 敏感性检测。通过实时定量 PCR、荧光原位杂交和免疫印迹在 34 种肺癌细胞系中检测 miRNA、FGFR1 信使 RNA、基因拷贝数和蛋白表达。
在 34 种细胞系中，有 14 种对 ponatinib 敏感，20 种对 AZD4547 敏感（引起 50%抑制的药物浓度值<100nmol/L）。从 4 对 ponatinib 敏感或不敏感的细胞系中最初鉴定出的 377-miRNA 组中的 39 种 miRNA 至少有 8 倍的差异表达，然后在所有 34 种细胞系中进行检测。开发了一个由 3 个 miRNA（let-7c、miRNA155 和 miRNA218）组成的预测性 miRNA-panel，其曲线下面积（AUC）为 0.886，对 ponatinib 的敏感性为 71.4%，特异性为 77.3%。miRNA-panel 的表现与 FGFR1 蛋白表达（AUC=0.864）和信使 RNA 表达（AUC=0.939）相似，优于 FGFR1 扩增（AUC=0.696）。此外，我们使用细胞系队列中对 AZD4547 敏感性的验证数据，该 miRNA-panel 的 AUC 为 0.931，敏感性为 73.3%，特异性为 76.2%。
该开发的 miRNA-panel（let-7c、miRNA155 和 miRNA218）可能有助于预测 FGFR 酪氨酸激酶抑制剂，无论是 ponatinib 还是 AZD4547 在肺癌细胞系中的反应，值得在临床环境中进一步验证。
