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Cellular and Molecular Biology

The novel FGFR inhibitor F1-7 induces DNA damage and cell death in colon cells

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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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Fig. 1: F1-7 inhibiting phosphorylation of FGFR in colon cancer.
Fig. 2: Colon cancer cells transcriptome level was influenced by F1-7.
Fig. 3: F1-7 induced colon cancer cells apoptosis and ferroptosis.
Fig. 4: F1-7 induced colon cancer cells DNA damage.
Fig. 5: Effects of F1-7 on colon cancer cell cycle.
Fig. 6: F1-7 showed promising efficacy to suppress colon cancer cells proliferation.
Fig. 7: The anti-tumour activity of F1-7 in vivo.
Fig. 8

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This study was supported by the National Natural Science Funding of China (81473242, 21877085 and 21602159).

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Authors

Contributions

YC and XZ contributed to the conception of the study; YL, LZ and XC performed the experiment; FH and XS revised and complemented the figure; DC and JS contributed significantly to analysis and manuscript preparation; YL performed the data analyses and wrote the manuscript; JW, QX and YX helped perform the analysis with constructive discussions.

Corresponding authors

Correspondence to Youqun Xiang, Xiaohui Zheng or Yuepiao Cai.

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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

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