Eph Receptors in Pancreatic Cancer: Biological Roles and Clinical Implications

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate of approximately 12%. Treatment options, including surgical resection and chemotherapy, are often ineffective in advanced stages due to late detection. This review examines the role of Erythropoietin-producing human hepatocellular (Eph) receptors in PDAC, emphasizing their potential both as therapeutic targets and biomarkers. Eph receptors, a family of receptor tyrosine kinases, are frequently overexpressed in various cancers and contribute to tumor growth, angiogenesis, and metastasis. Among the molecular drivers implicated in PDAC, EphA2, EphA4, EphA10, and EphB4, have emerged as key players in tumor progression, metastasis, resistance to therapy and poor prognosis. Eph receptor fragments show potential as early detection and prognostic biomarkers, potentially offering higher sensitivity than traditional markers such as CA 19-9. Additionally, emerging therapies targeting these receptors, such as EphA2-directed drug conjugates and small-molecule inhibitors, show promising results in preclinical models. Despite these advancements, their clinical translation remains limited, because of low specificity, poor delivery, and lack of validation in large patient cohorts. This review underscores the significance of Eph receptors in PDAC biology and highlights their dual utility as biomarkers and therapeutic targets, emphasizing the need for in depth investigation to bridge the gap between experimental promise and clinical reality. Harnessing Eph receptor biology holds the potential to improve early diagnosis and open new avenues for precision therapy and better treatment outcomes in one of the deadliest cancers.