Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug’s effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib’s mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.
胰腺癌的特征在于肿瘤微环境中存在纤维化/促结缔组织增生，这一过程主要由胰腺星状细胞和癌症相关成纤维细胞介导。HGF/c-MET信号通路在胚胎发育和伤口愈合中发挥重要作用，同时也因其促有丝分裂和促运动特性而备受关注。在胰腺癌中，该通路及其下游信号通路与疾病进展、预后、转移、化疗耐药性及其他肿瘤相关因素密切相关。胰腺癌微环境中与HGF/c-MET通路相关的其他特征包括缺氧、血管生成、转移以及尿激酶纤溶酶原激活剂正反馈循环。所有这些特性对胰腺癌的发生、进展和转移具有关键影响。因此，靶向HGF/c-MET信号通路有望为开发胰腺癌创新治疗药物提供新方向。c-MET激活的主要下游效应之一是MAPK/ERK（Ras、Ras/Raf/MEK/ERK）信号级联反应，而MEK（丝裂原活化蛋白激酶激酶）抑制剂已在RAS突变型黑色素瘤和肺癌中显示出治疗价值。曲美替尼是一种选择性MEK1和MEK2抑制剂，已成为针对多种恶性肿瘤（包括BRAF突变型黑色素瘤、非小细胞肺癌和甲状腺癌）中MAPK/ERK通路的关键治疗药物。当与BRAF抑制剂等药物联合使用时，其疗效显著增强。然而，耐药性仍是当前面临的挑战，需要持续研究以克服耐药机制。本综述深入探讨了HGF/c-MET信号通路、曲美替尼的作用机制、临床应用、联合治疗策略及其在胰腺癌治疗中的未来发展方向。
Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib
肿瘤(癌症)患者之家