دورية أكاديمية
Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma.
| العنوان: | Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma. |
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| المؤلفون: | Tai DWM; Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Le TBU; Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Prawira A; Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Ho RZW; Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Huynh H; Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore. cmrhth@nccs.com.sg. |
| المصدر: | Hepatology international [Hepatol Int] 2021 Oct; Vol. 15 (5), pp. 1236-1246. Date of Electronic Publication: 2021 Jul 31. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Country of Publication: United States NLM ID: 101304009 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1936-0541 (Electronic) Linking ISSN: 19360533 NLM ISO Abbreviation: Hepatol Int Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Springer |
| مواضيع طبية MeSH: | Carcinoma, Hepatocellular*/drug therapy , Liver Neoplasms*/drug therapy, Animals ; Cell Line, Tumor ; Fibroblast Growth Factors ; Humans ; Mice ; Mice, SCID ; Phenylurea Compounds ; Signal Transduction |
| مستخلص: | Background: Hepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. The overexpression of fibroblast growth factor (FGF) receptors (FGFRs) signaling cascade has been shown to contribute to tumorigenesis, metastasis, and poor prognosis in HCC. Therefore, targeted inhibition of the FGF/FGFR cascade may represent a new treatment strategy for HCC patients. Methods: HCC patient-derived xenograft (PDX) models were implanted into either severe combined immunodeficient (SCID) or CD34+hu-NSG (humanized) mice and subsequently treated with vehicle, infigratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of infigratinib and FGF401. Tumor progressions, overall survival of mice, lung metastasis, and drug resistance were monitored, and samples collected at the end of the treatment cycle were subjected to Western blot analyses and immunohistochemistry. Results: HCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and infigratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination infigratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination significantly increased the infiltration of B cells, macrophages, CD8+ T cells, and CD4+ T cells associated with granzyme-B-mediated apoptosis, delayed onset of resistance, and inhibited metastasis by potently inhibiting several critical signaling pathways involved in proliferation and metastasis. Conclusions: Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials. (© 2021. Asian Pacific Association for the Study of the Liver.) |
| References: | Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7–30. (PMID: 10.3322/caac.21387) Gordan JD, Kennedy EB, Abou-Alfa GK, Beg MS, Brower ST, Gade TP, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol 2020;38:4317–4345. (PMID: 10.1200/JCO.20.02672) Harimoto N, Taguchi K, Shirabe K, Adachi E, Sakaguchi Y, Toh Y, et al. The significance of fibroblast growth factor receptor 2 expression in differentiation of hepatocellular carcinoma. Oncology 2010;78:361–368. (PMID: 10.1159/000320463) Paur J, Nika L, Maier C, Moscu-Gregor A, Kostka J, Huber D, et al. Fibroblast growth factor receptor 3 isoforms: novel therapeutic targets for hepatocellular carcinoma? Hepatology 2015;62:1767–1778. (PMID: 10.1002/hep.28023) Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, et al. VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. J Cell Sci 2005;118:3759–3768. (PMID: 10.1242/jcs.02483) Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592–603. (PMID: 10.1038/nrc2442) Hyeon J, Ahn S, Lee JJ, Song DH, Park C-K. Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma. Dig Dis Sci 2013;58:1916–1922. (PMID: 10.1007/s10620-013-2609-x) Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu J-Y, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 2014;74:3306–3316. (PMID: 10.1158/0008-5472.CAN-14-0208) French DM, Lin BC, Wang M, Adams C, Shek T, Hotzel K, et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 2012;7:e36713. (PMID: 10.1371/journal.pone.0036713) Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening. Cancer Cell 2011;19:347–358. (PMID: 10.1016/j.ccr.2011.01.040) Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 2011;54:7066–7083. (PMID: 10.1021/jm2006222) Huynh H, Lee LY, Goh KY, Ong R, Hao H-X, Huang A, et al. Infigratinib mediates vascular normalization, impairs metastasis, and improves chemotherapy in hepatocellular carcinoma. Hepatology 2019;69:943–958. (PMID: 10.1002/hep.30481) Weiss A, Adler F, Buhles A, Stamm C, Fairhurst RA, Kiffe M, et al. FGF401, a first-in-class highly selective and potent FGFR4 inhibitor for the treatment of FGF19-driven hepatocellular cancer. Mol Cancer Ther 2019;18:2194–2206. (PMID: 10.1158/1535-7163.MCT-18-1291) Huynh H, Prawira A, Le TBU, Vu TC, Hao H-X, Huang A, et al. FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma. Exp Mol Med 2020;52:1857–1868. (PMID: 10.1038/s12276-020-00524-4) Chan SL, Yen C-J, Schuler M, Lin C-C, Choo SP, Weiss K-H, et al. Abstract CT106: Ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression. Cancer Res 2017;77:CT106LP. (PMID: 10.1158/0008-5472.CAN-17-0992) Guide for the Care and Use of Laboratory Animals, 8th edition. Washington (DC): The National Academies Press; 2011. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, et al. AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol 2010;52:79–87. (PMID: 10.1016/j.jhep.2009.10.008) Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299–309. (PMID: 10.1016/j.ccr.2005.09.005) Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 2002;35:834–842. (PMID: 10.1053/jhep.2002.32541) Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734–1736. (PMID: 10.1126/science.271.5256.1734) Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I, Welte T, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 2017;544:250–254. (PMID: 10.1038/nature21724) Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 2018;15:310–324. (PMID: 10.1038/nrclinonc.2018.9) Kurebayashi Y, Ojima H, Tsujikawa H, Kubota N, Maehara J, Abe Y, et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology 2018;68:1025–1041. (PMID: 10.1002/hep.29904) Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563–567. (PMID: 10.1038/nature14011) Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568–571. (PMID: 10.1038/nature13954) Chen P-L, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov 2016;6:827–837. (PMID: 10.1158/2159-8290.CD-15-1545) Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord J-P, Hidalgo M, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion St. J Clin Oncol 2017;35:157–165. (PMID: 10.1200/JCO.2016.67.2048) Dawkins J, Webster RM. The hepatocellular carcinoma market. Nat Rev Drug Discov 2019;18:13–14. (PMID: 10.1038/nrd.2018.146) Tallarida RJ. Drug synergism: its detection and applications. J Pharmacol Exp Ther 2001;298:865–872. (PMID: 11504778) |
| معلومات مُعتمدة: | NMRC/MOHIAFCAT2/006/2016 Singapore National Medical Research Council; NMRC/MOHIAFCat1/0026/2015 Singapore National Medical Research Council; NMRC/MOHIAFCat1/0009/2014 Singapore National Medical Research Council; CGAug16M005 RIE2020 NCIS Centre Grant; NRF-CRP17-2017-05 National Research Foundation Singapore |
| فهرسة مساهمة: | Keywords: Drug resistance; Fibroblast growth factor signaling pathway; Growth inhibition; Immune response; Liver cancer; Metastasis; Overall survival; PDX model; Preclinical study; Tumor hypoxia; Vascular normalization |
| المشرفين على المادة: | 0 (FGF19 protein, human) 0 (Phenylurea Compounds) 62031-54-3 (Fibroblast Growth Factors) |
| تواريخ الأحداث: | Date Created: 20210801 Date Completed: 20211125 Latest Revision: 20211125 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1007/s12072-021-10212-8 |
| PMID: | 34333737 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1936-0541 |
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| DOI: | 10.1007/s12072-021-10212-8 |