Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients.
First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7.
F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway.
F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.
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The data used to support the findings of this study are available from the corresponding author upon request.
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–91.
Murakawa T. Past, present, and future perspectives of pulmonary metastasectomy for patients with advanced colorectal cancer. Surg Today. 2021;51:204–11.
Cheng YD, Yang H, Chen GQ, Zhang ZC. Molecularly targeted drugs for metastatic colorectal cancer. Drug Des Devel Ther. 2013;7:1315–22.
Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21:2684–94.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10:1373.
Porta R, Borea R, Coelho A, Khan S, Araujo A, Reclusa P, et al. FGFR a promising druggable target in cancer: Molecular biology and new drugs. Crit Rev Oncol Hematol. 2017;113:256–67.
Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther. 2012;11:690–9.
Ma WW, Xie H, Fetterly G, Pitzonka L, Whitworth A, LeVea C, et al. A phase Ib study of the FGFR/VEGFR inhibitor dovitinib with gemcitabine and capecitabine in advanced solid tumor and pancreatic cancer patients. Am J Clin Oncol. 2019;42:184–9.
Guffanti F, Chila R, Bello E, Zucchetti M, Zangarini M, Ceriani L, et al. In vitro and in vivo activity of lucitanib in FGFR1/2 amplified or mutated cancer models. Neoplasia. 2017;19:35–42.
Steegmann JL, Baccarani M, Breccia M, Casado LF, Garcia-Gutierrez V, Hochhaus A, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648–71.
Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045–56.
Komla-Ebri D, Dambroise E, Kramer I, Benoist-Lasselin C, Kaci N, Le Gall C, et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest. 2016;126:1871–84.
Wu D, Guo M, Min X, Dai S, Li M, Tan S, et al. LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance. Chem Commun (Camb). 2018;54:12089–92.
Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53.
Lin S, Yang L, Yao Y, Xu L, Xiang Y, Zhao H, et al. Flubendazole demonstrates valid antitumor effects by inhibiting STAT3 and activating autophagy. J Exp Clin Cancer Res. 2019;38:293.
Qiu Y, Xiao Z, Wang Y, Zhang D, Zhang W, Wang G, et al. Optimization and anti-inflammatory evaluation of methyl gallate derivatives as a myeloid differentiation protein 2 inhibitor. Bioorg Med Chem. 2019;27:115049.
Lu HR, Meng LH, Huang M, Zhu H, Miao ZH, Ding J. DNA damage, c-myc suppression and apoptosis induced by the novel topoisomerase II inhibitor, salvicine, in human breast cancer MCF-7 cells. Cancer Chemother Pharmacol. 2005;55:286–94.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.
Wenger T, Miller D, Evans K. FGFR Craniosynostosis Syndromes Overview. In: MP Adam et al. (eds). GeneReviews®. October 20, 1998.
Liu Y, Cao M, Cai Y, Li X, Zhao C, Cui R. Dissecting the role of the FGF19-FGFR4 signaling pathway in cancer development and progression. Front Cell Dev Biol. 2020;8:95.
von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31:258–61.
Zhou L, Wang S, Cao L, Ren X, Li Y, Shao J, et al. Lead acetate induces apoptosis in Leydig cells by activating PPARgamma/caspase-3/PARP pathway. Int J Environ Health Res. 2021;31:34–44.
Maes ME, Grosser JA, Fehrman RL, Schlamp CL, Nickells RW. Completion of BAX recruitment correlates with mitochondrial fission during apoptosis. Sci Rep. 2019;9:16565.
Willis S, Day CL, Hinds MG, Huang DC. The Bcl-2-regulated apoptotic pathway. J Cell Sci. 2003;116:4053–6.
Kuo LJ, Yang LX. Gamma-H2AX—a novel biomarker for DNA double-strand breaks. Vivo. 2008;22:305–9.
Yang Y, Xue K, Li Z, Zheng W, Dong W, Song J, et al. [Corrigendum] cMyc regulates the CDK1/cyclin B1 dependentG2/M cell cycle progression by histone H4 acetylation in Raji cells. Int J Mol Med. 2019;44:1988.
Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014;34:280–300.
Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev. 2009;28:5–14.
Fuhrmann A, Banisadr A, Beri P, Tlsty TD, Engler AJ. Metastatic state of cancer cells may be indicated by adhesion strength. Biophys J. 2017;112:736–45.
Venetsanakos E, Brameld KA, Phan VT, Verner E, Owens TD, Xing Y, et al. The irreversible covalent fibroblast growth factor receptor inhibitor PRN1371 exhibits sustained inhibition of FGFR after drug clearance. Mol Cancer Ther. 2017;16:2668–76.
Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, et al. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc Natl Acad Sci USA. 2014;111:E4869–4877.
Lu X, Chen H, Patterson AV, Smaill JB, Ding K. Fibroblast growth factor receptor 4 (FGFR4) selective inhibitors as hepatocellular carcinoma therapy: advances and prospects. J Med Chem. 2019;62:2905–15.
Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, et al. Futibatinib is a novel irreversible FGFR 1-4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors. Cancer Res. 2020;80:4986–97.
Kang X, Lin Z, Xu M, Pan J, Wang ZW. Deciphering role of FGFR signalling pathway in pancreatic cancer. Cell Prolif. 2019;52:e12605.
This study was supported by the National Natural Science Funding of China (81473242, 21877085 and 21602159).
The authors declare no competing interests.
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Our study was approved by ‘the Laboratory Animal Centre, Wenzhou Medical University’ (wydw2020-0886).
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Liu, Y., Zhang, L., Chen, X. et al. The novel FGFR inhibitor F1-7 induces DNA damage and cell death in colon cells. Br J Cancer 127, 1014–1025 (2022). https://doi.org/10.1038/s41416-022-01878-4