The emerging role of AXL in pancreatic cancer: Biomarker potential and therapeutic targeting to counteract drug resistance

Resistance to therapy is a major driver of the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), which is projected to become the second leading cause of cancer-related death by 2030. The lack of reliable biomarkers for early detection and the rapid emergence of therapeutic resistance underscore an urgent need for strategies capable of improving patient stratification and overcoming treatment failure. In this context, the receptor tyrosine kinase AXL has gained increasing attention as a mediator of PDAC progression, sustaining tumor cell survival and plasticity while fostering an immunosuppressive, fibrotic microenvironment, that collectively fuels resistance to both cytotoxic and targeted therapies. In this review, we critically evaluate the therapeutic landscape of AXL inhibition in PDAC. We discuss the spectrum of pharmacological approaches under investigation, including small-molecule inhibitors, monoclonal antibodies, and ligand-blocking agents, alongside emerging modalities such as antibody-drug conjugates, bispecific formats, and CAR-T cell platforms, emphasizing both their promise and the persistent barriers of limited tumor penetration and stromal resistance. Furthermore, we highlight the growing interest in AXL as a circulating biomarker, with potential applications in early patient selection, dynamic treatment monitoring, and prediction of resistance. By integrating mechanistic insights with translational advances, this review outlines both the opportunities and the barriers that will shape the future of AXL-directed strategies in PDAC and their potential to address current gaps in therapeutic resistance.