FGFR2 Colorimetric Cell-Based ELISA Kit

Objective: The aim of this study was to evaluate whether estrogen promoted the proliferation and invasion of endometrial carcinoma (EC) cells through paracrine FGFs in endometrial stromal cells (ESCs). Patients and Methods: We screened gene alterations in a primary ESC culture after 10 nM estrogen treatment using an Agilent mRNA microarray. We knocked down stromal FGF18 expression in a co-culture system and aimed to explore the contribution of E2-induced stromal FGF18 to the proliferation and invasion of EC cells. To determine the effective receptors and detailed downstream signaling of FGF18, we co-cultured estrogen-treated hESCs with FGFR1-, FGFR2-, FGFR3- or FGFR4-knockdown Ishikawa cells. Finally, we detected FGF18 expression in clinical samples, including several primary cultures of different ESCs and a series of tissue microarrays (TMAs) of 90 patients with EC. Results: A few genes altered significantly in estrogen-treated primary ESCs, but only FGF18 was noticeably enhanced among the FGF family genes. Knockdown of FGF18 expression in hESCs inhibited the promoting effect of FGF18 on the proliferation and invasion of EC cells. FGF18 bound FGFR2 and FGFR3 in Ishikawa cells to activate downstream ERK and Akt pathways and to promote the viability of EC cells. The FGF18-FGFR2 and FGF18-FGFR3 pathways had close correlations with Survivin and CD44V6 expression but not with P53. Primary ESCs of endometrioid EC (EEC, type I EC) had higher FGF18 expression than ESCs of normal endometrium (NE), endometrial atypical hyperplasia (EAH) and type II EC. Conclusion: Estrogen induced FGF18 in ESCs to promote the proliferation and invasion of EC cells, and FGFR inhibitors should be considered as promising candidate targets for EC treatment.

BACKGROUND: Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. METHODS: This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. RESULTS: Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade >= 3 AEs occurred in 8 patients (27.6%). CONCLUSION: Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).