The Receptor Tyrosine Kinase Axl in (Advanced) Gastric Cancer-From Pathophysiology to Therapeutic Impact

Background: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with its advanced stages presenting significant challenges for the clinical oncologist. Axl is a member of the TAM family of receptor tyrosine kinases that is becoming increasingly important in the pathophysiology of (advanced) GC. This receptor, activated by its ligand Gas6 (growth arrest-specific gene 6), is implicated in various oncogenic processes, including cell survival, proliferation, migration, and immune evasion. Overexpression or aberrant activation of Axl has been associated with poor prognosis, tumor aggressiveness, and resistance to conventional therapies in gastric cancer. Objectives: This review aims to consolidate current knowledge on Axl's role in gastric cancer pathophysiology and explore its therapeutic implications. Materials and Methods: A thorough search was conducted in the most relevant online databases, using different combinations of the following terms: Axl, GC, pathophysiology, and therapeutic target. Results: In the first part, the molecular mechanisms of Axl in tumors, which involve, among others, the activation of downstream signaling pathways, including PI3K/AKT, MAPK/ERK, and NF-κB, are discussed. Subsequently, potential treatments targeting Axl and potential combination therapies are highlighted, based on the encouraging results from preclinical and clinical studies. Finally, as the Axl-tumor microenvironment interplay is discussed, with therapeutic implications, it thus opens new pathways for research on effective treatments in advanced gastric cancer. Conclusions: Understanding Axl's role in the pathophysiology of GC is essential to develop efficient targeted therapies with improved clinical effects.