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.

激活 ERK 激酶的KRAS和/或BRAF突变常见于结直肠癌 (CRC) 并导致对靶向治疗的耐药性。因此，识别同时影响多个信号通路的治疗靶点对于改善KRAS或BRAF突变患者的治疗至关重要。前蛋白转化酶弗林蛋白酶通过内切蛋白裂解激活几种参与 ERK-MAPK 途径的致癌蛋白前体。在这里，我们表明弗林蛋白酶的遗传失活抑制了KRAS或BRAF突变 CRC 细胞系中的致瘤性生长、增殖和迁移，但在野生型KRAS和BRAF细胞。在小鼠异种移植模型中，这些缺乏弗林蛋白酶的KRAS或BRAF突变细胞表现出生长和血管生成减少，以及细胞凋亡增加。从机制上讲，弗林蛋白酶失活阻止了各种蛋白质前体的加工，包括 proIGF1R、proIR、proc-MET、proTGF-β1 和 NOTCH1，从而导致KRAS或BRAF突变细胞中有效且持久的 ERK-MAPK 通路抑制。此外，我们鉴定了参与激活 ERK-MAPK 通路的基因，例如PTGS2，它们在弗林蛋白酶失活后在KRAS或BRAF突变细胞中下调，但在野生型KRAS和BRAF中上调细胞。对人类结直肠肿瘤样本的分析揭示了增强的弗林蛋白酶表达与KRAS或BRAF表达之间的正相关。这些结果表明弗林蛋白酶在KRAS或BRAF相关的 ERK-MAPK 通路激活和肿瘤发生中起重要作用，为个性化治疗提供了潜在的靶点。