A miRNA Panel Predicts Sensitivity of FGFR Inhibitor in Lung Cancer Cell Lines

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: AZD4547; biomarker; lung cancer; miRNA; ponatinib.

Figure 1.

Receiver operating curves (ROCs) for the developed miRNA (let-7c, miR-155, and miR-218) together with FGFR1 mRNA, protein expression and amplification to predict the sensitivity of ponatinib (Figure 1A, on the left) and AZD4547 (Figure 1B, on the right) by using the IC50 cutoff values 100 nmol/l.

Figure 2.

Receiver operating curves (ROCs) for the developed miRNA (let-7c, miR-155, and miR-218 to predict the sensitivity of ponatinib (Figure 2A, on the left, AUC=0.853) and AZD4547 (Figure 2B, on the right, AUC=0.865) by using the IC50 cutoff values 50 nmol/l.