Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
Interdisciplinary Research Facility, Department of Development and Regeneration, KU Leuven, Campus Kulak Kortrijk, Kortrijk, Belgium.
Oncogene. 2020 Apr;39(17):3571-3587. doi: 10.1038/s41388-020-1238-z. Epub 2020 Mar 6.
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.
KRAS 和/或 BRAF 中的突变会激活 ERK 激酶，这在结直肠癌 (CRC) 中经常发现，并导致对靶向治疗的耐药性。因此，鉴定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。蛋白原转化酶 furin 通过内切酶切割激活几种参与 ERK-MAPK 通路的致癌蛋白前体。在这里，我们表明 furin 的遗传失活抑制了 KRAS 或 BRAF 突变 CRC 细胞系中的肿瘤发生生长、增殖和迁移，但对野生型 KRAS 和 BRAF 细胞没有影响。在小鼠异种移植模型中，这些缺乏 furin 的 KRAS 或 BRAF 突变细胞显示出生长和血管生成减少，凋亡增加。在机制上，furin 失活阻止了包括 proIGF1R、proIR、proc-MET、proTGF-β1 和 NOTCH1 在内的多种蛋白前体的加工，导致 KRAS 或 BRAF 突变细胞中 ERK-MAPK 通路的强烈和持久抑制。此外，我们鉴定了参与激活 ERK-MAPK 通路的基因，例如 PTGS2，在 furin 失活后 KRAS 或 BRAF 突变细胞中下调，但在野生型 KRAS 和 BRAF 细胞中上调。对人类结直肠肿瘤样本的分析表明，增强的 furin 表达与 KRAS 或 BRAF 表达之间存在正相关。这些结果表明 furin 在 KRAS 或 BRAF 相关的 ERK-MAPK 通路激活和肿瘤发生中发挥重要作用，为个性化治疗提供了潜在的靶点。
