Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1

Abstract

Abstract. Lung cancer is still the leading cause of cancerrelated deaths worldwide. Identifying new oncogenic drivers and developing efficient inhibitors through molecular targeting approaches are crucial for improving therapies. The aim of this study was to investigate whether targeting fibroblast growth factor receptor 1 (FGFR1) with ponatinib inhibits the cell growth in both established and primary lung cancer cells overexpressing FGFR1. Eighty-eight non-small cell lung cancer (NSCLC) and paired normal tissue specimens were analyzed by real-time RT-PCR for FGFR1 gene expression. We identified four cell lines and two newly established primary lung cancer cultures that showed high FGFR1 expression levels, and evaluated the effect of the novel FGFR1 inhibitor ponatinib on cell growth. Approximately 50% (30 out of 59) NSCLC specimens expressed FGFR1 >2-fold compared with their adjacent normal counterparts using quantitative RT-PCR. Ponatinib treatment of established NSCLC cell lines expressing higher levels of FGFR1 resulted in marked cell growth inhibition and suppression of clonogenicity. This growth inhibition was associated with inactivation of FGFR1 and its downstream targets. FGFR1 knockdown by shRNA achieved similar results when compared to treatment with ponatinib. Furthermore, ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1.

Increased gene copy number of HER2 and concordant protein overexpression found in a subset of eyelid sebaceous gland carcinoma indicate HER2 as a potential therapeutic target

“…FGFR inhibitors demonstrated marked cell growth inhibition and suppression of clonogenicity in the non-small cell lung cancer cell line (Ren et al 2013). We found the amplification of this gene in approximately 12 % of the patients with eyelid SbGC, at a low level.…”

Fibroblast Growth Factor Receptor 1 Gene Copy Number and mRNA Expression in Primary Colorectal Cancer and Its Clinicopathologic Correlation

“…Recently, many studies have reported that FGFR1 GCN alteration could serve as the basis for FGFR-targeted therapy [17,18,30,31]. On the other hand, Wynes et al [32] found that FGFR tyrosine kinase inhibitor sensitivity is not correlated with GCN but rather with mRNA and protein expression in lung cancer, suggesting a crucial role of mRNA and protein expression status in FGFR-targeted therapy.…”

“…Preclinical studies have shown that the growth of non-small cell lung cancer and breast cancer cell lines is suppressed by FGFR-specific inhibitors [17,18]. FGFR1 GCN alteration was observed in up to 5% of CRCs according to prior studies, although this prevalence is lower than that reported for other malignancies [19,20,21].…”

FGFR1 amplification in lung squamous cell carcinoma: A systematic review with meta-analysis

“…Fourteen studies were excluded after full text assessment for eligibility. A total of 13 studies [19][20][21][22][23][24][25][26][27][28][29][30][31] met the eligibility criteria and were included in this systematic review.…”