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Open AccessArticle

FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer

1
Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan
2
Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
3
Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan
4
Oncology Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa 761-0793, Japan
5
Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan
6
Department of Comprehensive Education in Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan
7
Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
8
Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA 92697, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 2976; https://doi.org/10.3390/cancers12102976
Received: 28 September 2020 / Accepted: 6 October 2020 / Published: 14 October 2020
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
Pancreatic 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). View Full-Text
Keywords: FGFR4; pancreatic cancer; FGFR4 inhibitor; growth; invasion; senescence; senolytic therapy FGFR4; pancreatic cancer; FGFR4 inhibitor; growth; invasion; senescence; senolytic therapy
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MDPI and ACS Style

Sasaki, N.; Gomi, F.; Yoshimura, H.; Yamamoto, M.; Matsuda, Y.; Michishita, M.; Hatakeyama, H.; Kawano, Y.; Toyoda, M.; Korc, M.; Ishiwata, T. FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer. Cancers 2020, 12, 2976. https://doi.org/10.3390/cancers12102976

AMA Style

Sasaki N, Gomi F, Yoshimura H, Yamamoto M, Matsuda Y, Michishita M, Hatakeyama H, Kawano Y, Toyoda M, Korc M, Ishiwata T. FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer. Cancers. 2020; 12(10):2976. https://doi.org/10.3390/cancers12102976

Chicago/Turabian Style

Sasaki, Norihiko; Gomi, Fujiya; Yoshimura, Hisashi; Yamamoto, Masami; Matsuda, Yoko; Michishita, Masaki; Hatakeyama, Hitoshi; Kawano, Yoichi; Toyoda, Masashi; Korc, Murray; Ishiwata, Toshiyuki. 2020. "FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer" Cancers 12, no. 10: 2976. https://doi.org/10.3390/cancers12102976

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