Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib

Simple Summary Pancreatic cancer, notorious for its aggressive nature and complex desmoplastic tumor microenvironment, poses substantial treatment challenges, particularly in terms of early detection, and often exhibits resistance to standard chemotherapy and immunotherapy. Trametinib is a new therapeutic drug, a selective inhibitor of MEK1 and MEK2, which has shown promise in addressing these challenges. It not only hampers cancer cell division, angiogenesis, and metastatic spread but also significantly modifies the tumor microenvironment. This modification includes altering the activities of fibroblasts and immune cells, which are crucial in the cancer's progression and response to treatments. Several pivotal studies have highlighted trametinib's efficacy in reducing the proliferation of pancreatic cancer cells and enhancing the effectiveness of combined treatment regimens, especially in cases that show resistance to conventional therapies. The drug's potential to improve patient outcomes is currently under investigation in various clinical trials. These trials, encompassing different stages and forms of pancreatic cancer, are instrumental in determining the optimal use of trametinib, both as a single agent and in combination with other drugs. The ongoing research is crucial in defining trametinib's role in the evolving therapeutic landscape for pancreatic cancer, aiming to provide new avenues for treatment and potentially improve survival rates in this challenging disease area.Abstract 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.