Mutations in KRAS and/or BRAF that activate the ERK kinase are frequently found in colorectal cancer (CRC) and drive resistance to targeted therapies. Therefore, the identification of therapeutic targets that affect multiple signaling pathways simultaneously is crucial for improving the treatment of patients with KRAS or BRAF mutations. The proprotein convertase furin activates several oncogenic protein precursors involved in the ERK-MAPK pathway by endoproteolytic cleavage. Here we show that genetic inactivation of furin suppresses tumorigenic growth, proliferation, and migration in KRAS or BRAF mutant CRC cell lines but not in wild-type KRAS and BRAF cells. In a mouse xenograft model, these KRAS or BRAF mutant cells lacking furin displayed reduced growth and angiogenesis, and increased apoptosis. Mechanistically, furin inactivation prevents the processing of various protein pecursors including proIGF1R, proIR, proc-MET, proTGF-β1 and NOTCH1 leading to potent and durable ERK-MAPK pathway suppression in KRAS or BRAF mutant cells. Furthermore, we identified genes involved in activating the ERK-MAPK pathway, such as PTGS2, which are downregulated in the KRAS or BRAF mutant cells after furin inactivation but upregulated in wild-type KRAS and BRAF cells. Analysis of human colorectal tumor samples reveals a positive correlation between enhanced furin expression and KRAS or BRAF expression. These results indicate that furin plays an important role in KRAS or BRAF-associated ERK-MAPK pathway activation and tumorigenesis, providing a potential target for personalized treatment.
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All raw RNA-sequencing data can be found at the NCBI Gene Expression Omnibus (accession number: GSE130969). Raw data for figures are available as source data to the relevant figure. All other datasets generated and analyzed during the current study are available from the corresponding authors upon reasonable request. Any requests for data or materials should be addressed to JC.
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We would like to thank Maria Francesca Baietti for providing help with the soft agar assay, and Rudra Kashyap for providing help with the wound healing migration assay. We would also like to thank Álvaro Cortés Calabuig for the RNA-seq data analysis. This work was supported in part by SIRIC BRIO and La Ligue Contre le Cancer to AMK, France. We acknowledge grant support from FWO Vlaanderen (Grant nr.G.0738.15) to JC. ZH was supported by a Chinese Government Scholarship (Nr. 201409110101).
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He, Z., Thorrez, L., Siegfried, G. et al. The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer. Oncogene 39, 3571–3587 (2020). https://doi.org/10.1038/s41388-020-1238-z
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