Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that is projected to become the leading cause of cancer death by 2050. Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor that is overexpressed in half of PDACs. We determined that its expression in PDAC positively correlated with larger tumor size and more advanced tumor stage, and that BLU9931, a selective FGFR4 inhibitor, reduced PDAC cell proliferation and invasion while promoting their senescence. Quercetin, a senolytic drug, induced cell death in BLU9931-treated cells. We propose that targeting FGFR4 in combination with senolysis could provide a novel therapeutic strategy in patients whose PDAC expresses high FGFR4 levels. Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, FGFR4 expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, FGFR4 was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in FGFR4 was detected. For inhibition of autocrine/paracrine FGF19/FGFR4 signaling, we used BLU9931, a highly selective FGFR4 inhibitor. Inhibition of signal transduction through ERK, AKT, and STAT3 pathways by BLU9931 reduced proliferation in FGF19/FGFR4 signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/FGFR4 signaling-activated PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in FGFR4-positive PDAC, especially when combined with senolysis (195/200).
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a 5-year survival rate of~9% [1]
Strong Fibroblast growth factor receptor 4 (FGFR4) immunoreactivity was seen in the cancer cells in 67 of 136 (49%) PDAC samples and high FGFR4 expression correlated with larger primary tumor size and more advanced stages of the cancer (p < 0.001, Table 1)
3F and S3E), suggesting that autocrine/paracrine FGF19/FGFR4 signaling upregulates FGF19 expression through the FGF19/FGFR4 signaling feedback loop. These results indicate that the inhibitory effect of 2 μM BLU9931 on PDAC cell proliferation is caused by inhibition of autocrine/paracrine FGF19/FGFR4 signaling and not through induction of apoptosis
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a 5-year survival rate of~9% [1]. PDAC is projected to become the leading cause of cancer death by 2050 [3]. 80% of PDAC patients are inoperable at diagnosis. Despite the development of non-surgical therapies, including chemotherapy, radiotherapy, and chemoradiotherapy, many of these patients die less than 6 months following diagnosis. Most FGFs are heparin binding, but FGF19, FGF21, and FGF23 do not have a heparin-binding domain and exhibit a low affinity for heparan sulfates [8]. These three FGFs are viewed as hormones rather than growth factors since they are readily released into the systemic circulation and modulate metabolic functions [8]
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