br Introduction The fibroblast growth factor receptor FGFR

Introduction The fibroblast growth factor receptor (FGFR) pathway is an important oncogenic driver in malignant cancer. It controls cellular processes such as cell proliferation, differentiation, migration, lgk974 progression, metabolism, and survival. In non–small-cell lung cancer, the most frequent alteration of the FGFR pathway is represented by FGFR1 amplification, which is reported as occurring in up to 20% of squamous non–small-cell lung cancer; other, less frequent alterations include point mutations or translocations of the genes encoding for FGFR1-4. Currently, several FGFR inhibitors are being investigated in phase 1-3 clinical trials in solid tumors with FGFR amplification or protein overexpression, such as nintedanib (Boehringer Ingelheim, Ingelheim am Rhein, Germany), ponatinib (Ariad Pharmaceuticals, Cambridge, MA), AZD4547 (AstraZeneca, London, UK), and BJG398 (Novartis, Basel, Switzerland). In these studies, preliminary results showed that only a subset of patients with FGFR amplification or protein overexpression had disease that responded to the FGFR tyrosine kinase inhibitors (TKIs) AZD4547 and BJG003.5, 6 The response rates did not reach those observed for other lung cancer driver mutation genes, such as mutant EGFR or ALK/ROS1 fusion, suggesting that the biomarkers used for enrolling onto the FGFR TKI trials were inaccurate. In a set of 58 lung cancer cell lines, sensitivity to ponatinib was correlated with FGFR1 amplification, messenger RNA (mRNA) and protein expression, and mRNA expression of FGF2 and FGF9. This study reported better correlation of FGFR1 TKI sensitivity with FGFR1 mRNA or protein expression compared to FGFR1 amplification. These data clearly identify the need for further investigation to find additional biomarkers that may be better able to predict response to FGFR inhibitors in the clinical setting. MicroRNAs (miRNAs) are small, noncoding, stable sequences of RNA with regulatory functions exerted through inhibition of crucial mRNA. Recent studies demonstrated that pathologic conditions, such as solid tumors, are associated with specific intracellular miRNA patterns and are also able to affect circulating miRNA. On the basis of this assumption, several studies have identified specific miRNAs or groups of miRNAs (miRNA signatures) with a potential diagnostic or prognostic role in solid tumors.10, 11 Some miRNAs, such as miR-34bc, are currently considered promising predictors of poor outcome for early-stage lung cancer, apparently as a result of a correlation between their target genes inactivation and an aggressive phenotype. Another study suggested the existence of a circulating miRNA signature able to detect lung cancer. Furthermore, our previous study also found miRNA signatures were also reported as able to predict the sensitivity of lung cancer to epidermal growth factor receptor (EGFR) TKIs.14, 15 In this present study, we performed a comprehensive analysis of miRNAs in a panel of human lung cancer cell lines that were previously characterized for sensitivity to 2 FGFR1 TKIs. We developed a 3-miRNA panel that accurately predicts the sensitivity to ponatinib in 34 cell lines and the chemically distinct TKI, AZD4547.
Methods
Results
Discussion Precision therapy, guided by biomarkers of response, has dramatically improved the prognosis of patients with advanced lung cancer. Examples include mutant EGFR that can be effectively inhibited by EGFR TKIs, and deficient mismatch repair and high microsatellite instability, which are susceptible to anti–PD-1 immunotherapy.20, 21, 22 In this study, we investigated the role of miRNAs as a biomarker to predict sensitivity to FGFR inhibitors. Analysis revealed differences in the miRNA expression between cell lines determined to be sensitive and resistant to ponatinib with identification of a predictive miRNA panel including let-7c, miRNA155, and miRNA218. Analysis of this panel identified an AUC of 0.886 to predict sensitivity to ponatinib, which is as good as other predictive biomarkers including FGFR1 mRNA and protein expression, as previously reported. Furthermore, the predictive role of this miRNA panel was validated when comparing sensitivity of AZD4547 in the cell line cohort. Moreover, we found that the mechanism of let-7c to predict the sensitivity of ponatinib may involve regulating the mRNA expression of FGFR1.