Abstract A088: EphA2 Proteolytic Fragment Links Early Detection, IPMN Progression, and Therapeutic Resistance in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal because most patients are diagnosed after curative intervention is no longer feasible and resistance to systemic therapy is common. Intraductal papillary mucinous neoplasms (IPMNs) are important PDAC precursor lesions, but serum biomarkers for early PDAC detection, malignant IPMN progression, and therapeutic stratification remain limited. We previously identified a soluble N-terminal EphA2 fragment (EphA2-NF), generated by membrane-type 1 matrix metalloproteinase (MT1-MMP)-dependent EphA2 processing, as a candidate serum biomarker for pancreatic cancer (Cancer Res, 2015, Cell Death & Dis, 2018). Here, we investigated whether EphA2 proteolytic processing provides a biologically linked biomarker axis for early detection, IPMN surveillance, and prediction of therapeutic resistance in PDAC. Serum EphA2-NF levels were retrospectively evaluated in approximately 500 sera from patients with PDAC, including stage I/II disease and IPMN-associated pancreatic neoplasia. Associations between serum EphA2-NF and response to standard pancreatic cancer therapy were assessed (Cancer Res Commun 2023). EphA2 processing and downstream signaling were also analyzed in cancer models expressing MT1-MMP and EphA2 (Cell Death & Dise, in press). Retrospective clinical analyses showed that serum EphA2-NF detected early-stage PDAC, including stage I/II disease, supporting its utility as a blood-based marker for early pancreatic cancer detection. An increased deficiency of the N-terminal portion of EphA2 has also been observed in IPMN-associated pancreatic tumor formation, suggesting activation of EphA2 processing in the early stages of malignant transformation from precursor lesions. Importantly, patients with high serum EphA2-NF showed reduced responsiveness to gemcitabine plus nab-paclitaxel, indicating that EphA2-NF may identify a therapeutically resistant PDAC subset. Mechanistically, MT1-MMP-mediated EphA2 cleavage released EphA2-NF and generated membrane-retained C-terminal fragments (EphA2-CF). Complementary mechanistic studies demonstrated that EphA2-CF induces sustained EphA2-S897phosphorylation and AKT activation, leading to inhibitory phosphorylation and functional suppression of GSK3β. This signaling rewiring provides a plausible biological basis for the association between high serum EphA2-NF, malignant progression, and resistance to gemcitabine plus nab-paclitaxel therapy. These findings suggest that EphA2-NF is not merely a passive shedding product but a circulating biomarker generated through oncogenic receptor processing. MT1-MMP-dependent EphA2 processing may represent a clinically actionable biomarker axis for early PDAC detection, IPMN surveillance, prediction of gemcitabine plus nab-paclitaxel resistance, and future therapeutic intervention strategies.