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

Abstract

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.

• Authors: Yuqing Zhang, Emily N Arner, Ali Rizvi, Jason E Toombs, Huocong Huang, Steven L Warner, Jason M Foulks, Rolf A Brekken
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 21 Issue 1 Pg. 38-47 (01 2022) ISSN: 1538-8514 [Electronic] United States
• PMID: 34675118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Proto-Oncogene Proteins
• Pyrimidines
• Sulfonamides
• dubermatinib
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase

Topics

• Animals
• Cell Line, Tumor
• Humans
• Immunotherapy (methods)
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms (drug therapy, mortality, pathology)
• Proto-Oncogene Proteins (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)
• Survival Analysis
• Tumor Microenvironment
• Axl Receptor Tyrosine Kinase