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

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.

Keywords: pancreatic cancer; trametinib; tumor microenvironment.

Figure 1

Here, the major downstream signaling pathways of HGF/c-MET and targets of trametinib are shown. MET triggers several downstream signaling pathways: the Ras pathway, the PI3K–Akt pathway, and the STAT3 pathway. Trametinib targets the Ras (Ras/Raf/MEK/ERK, MAPK) pathway in various malignancies. HGF, hepatocyte growth factor; SHP2, SH2 domain-containing tyrosine phosphatase 2; SHC, SH2 domain-containing transforming protein; GRB2, growth factor receptor-bound protein 2; SOS, son of sevenless; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinases; PI3K, Phosphoinositide 3-kinase; Akt, protein kinase B; BAD, BCL-2 antagonist of cell death; MDM2, murine double minute 2; STAT3, Signal transducer and activator of transcription 3.

Figure 2

The figure shows tumor microenvironment remodeling by trametinib in pancreatic cancer. Trametinib induces significant alterations in the tumor microenvironment of pancreatic cancer. 1. Fibroblast Changes: (1) Decrease in myofibroblast-like cancer-associated fibroblasts (myoCAF). (2) Increase in inflammatory cancer-associated fibroblasts (iCAF). 2. Tgfb1 Expression: (1) Reduces Tgfb1 expression in myoCAF. 3. T Cell Responses: (1) Decrease in CD8+ and CD4+ T cells with gene expression resembling naive T cells. (2) Increase in T cells exhibiting functional cytotoxic, effector, and memory gene expression in mesenchymal pancreatic cancer.