AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer

by Selleckchem | Jul 02 2023

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States with a 5-year survival less than 5%. Resistance to standard therapy and limited response to immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment remain major challenges in the treatment of pancreatic cancer. A key cellular program involved in therapy resistance is epithelial plasticity, which is also associated with invasion, metastasis, and evasion of immune surveillance. The receptor tyrosine kinase AXL is a key driver of tumor cell epithelial plasticity. High expression and activity of AXL is associated with poor prognosis, metastasis, and therapy resistance in multiple types of cancer including pancreatic. Here, we show that an AXL inhibitor (TP-0903), has antitumor and therapy sensitizing effects in preclinical models of pancreatic ductal adenocarcinoma (PDA). We demonstrate that TP-0903 as a single agent or in combination with gemcitabine and/or anti-programmed cell death protein 1 (PD1) antibody has anti-metastatic and anti-tumor effects in PDA tumor bearing mice, leading to increased survival. In addition, gene expression analysis of tumors demonstrated upregulation of pro-inflammatory and immune activation genes in tumors from TP-0903-treated animals compared with the vehicle, indicating pharmacologic inhibition of AXL activation leads to an immunostimulatory microenvironment. This effect was augmented when TP-0903 was combined with gemcitabine and anti-PD1 antibody. These results provide clear rationale for evaluating TP-0903 in the treatment of pancreatic cancer.

Comments:

The passage you provided discusses the challenges associated with pancreatic cancer treatment and highlights the potential of an AXL inhibitor called TP-0903 in addressing these challenges. Pancreatic cancer is known to have a high mortality rate, with limited response to standard therapy and immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment of the tumor.

Epithelial plasticity, which is associated with therapy resistance, invasion, metastasis, and evasion of immune surveillance, plays a key role in pancreatic cancer. AXL, a receptor tyrosine kinase, is identified as a driver of tumor cell epithelial plasticity. High expression and activity of AXL have been correlated with poor prognosis, metastasis, and therapy resistance in various types of cancer, including pancreatic cancer.

The study mentioned in the passage demonstrates the potential of TP-0903, an AXL inhibitor, in preclinical models of pancreatic ductal adenocarcinoma (PDA). The researchers found that TP-0903, either as a single agent or in combination with gemcitabine (a chemotherapy drug) and/or an anti-programmed cell death protein 1 (PD1) antibody, showed antitumor and therapy sensitizing effects in mice with PDA tumors. This led to increased survival in the treated animals.

Furthermore, gene expression analysis of tumors from TP-0903-treated animals showed the upregulation of pro-inflammatory and immune activation genes compared to the control group. This indicates that pharmacological inhibition of AXL activation with TP-0903 promotes an immunostimulatory microenvironment within the tumors. The immunostimulatory effect was enhanced when TP-0903 was combined with gemcitabine and anti-PD1 antibody.

These findings provide a strong rationale for further evaluation of TP-0903 as a potential treatment for pancreatic cancer. The results suggest that TP-0903 could have both antitumor and immunostimulatory effects, making it a promising candidate for overcoming therapy resistance and improving patient outcomes in pancreatic cancer.