Validation of AXL as a Therapeutic Target in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the US, has a high metastatic rate that is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, has been identified as a critical factor that drives metastasis and immune suppression in many cancer types. Here we demonstrate that AXL-deficient PDA bearing mice have longer median survival, smaller tumors, fewer metastases and higher sensitivity to gemcitabine treatment compared to AXL wild-type (WT) PDA mice. AXL-deficient PDA displays a more differentiated histology, lower equilibrative nucleoside transporter 1 expression and has a more inflammatory and active immune microenvironment, all of which likely contribute to improved survival. As a result, AXL-deficient PDA treated with gemcitabine show more DNA damage (γH2AX) compared to WT PDA treated with gemcitabine. Single cell RNA sequencing of PDA genetically engineered mouse models reveals that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and AXL expression correlates with classic markers of mesenchymal tumor cells. This AXL-positive mesenchymal PDA cell population is critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target for pancreatic cancer patients. Multiple pharmacological strategies to inhibit AXL have been explored in pre-clinical models of PDA with promising therapeutic efficacy and similar phenotypes as genetically manipulation of AXL. These results provide a robust rationale for clinical studies aimed at investigating the effect of AXL inhibition in conjunction with standard therapy in pancreatic cancer patients.

Author dc:creator

• Du, Wenting

Contributors dc:contributor

• Malladi, Srinivas
• Brekken, Rolf A.
• Whitehurst, Angelique Wright
• Malter, James

• Molecular Targeted Therapy
• Pancreatic Neoplasms
• Proto-Oncogene Proteins
• Receptor Protein-Tyrosine Kinases

Language dc:language

en

Identifier

1290684145

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/9647