IRE1a as a prognostic marker and therapeutic target in Pancreatic Ductal Adenocarcinoma (PDAC)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options and poor prognosis. Current treatment options remain limited, urging for better understanding of the molecular mechanisms in PDAC. Cells from PDAC tumors face significant ER stress due to increased secretory demand, oncogenic activation and the tumor microenvironment. The unfolded protein response (UPR), a cellular stress response that helps manage unfolded proteins in the endoplasmic reticulum (ER) is of paramount importance in this context. The Inositol requiring enzyme 1 alpha (IRE1a) arm of UPR has emerged as a promising target for therapeutic intervention. However, its role in PDAC remains insufficiently explored.

Objectives: This study aims to evaluate IRE1a as a prognostic marker in patients with PDAC and to explore its potential as a therapeutic target.

Methods: IRE1a knockdown was introduced using shRNA interference. Viability and apoptosis was measured using glow assays. RNA sequencing was utilised to study effect of IRE1a knockdown in PDAC cells. Western blotting was used to validate alterations in key proteins. An IRE1a dependent signature, dubbed PRIME (Pancreatic cancer Response to IRE1 Mediated stress), was established to stratify patients into risk groups.

Results: IRE1a knockdown resulted in reduction of cell viability and increase in apoptosis that could not be rescued by apoptosis inhibition using Z-VAD-FMK. RNA sequencing revealed downregulation of cell cycle and validated upregulation of apoptosis pathway. Western blotting confirmed reduction in cell cycle related proteins phosphor-r retinoblastoma (pRb), and tumor protein 53 (p53) expression, upregulation of cell cycle attenuator cyclin dependent kinase 1 B (p27). Simultaneous downregulation of phospho-protein kinase B ser473 (pAKT^ser473) might be the link between IRE1a kd and p27 mediated cell cycle arrest. Survival analysis using from a combined cohort of TCGA-PAAD and ICGC-PACA-AU provided a list of 9 genes. A risk score derived from this 9-gene signature significantly stratified patients into high- and low-risk groups, with median survival times of 515 and 919 days.

Conclusions: This study establishes IRE1a as a crucial regulator of PDAC cell viability and cell cycle arrest. The association between IRE1a knockdown and patient survival highlights its potential as both a prognostic biomarker and a therapeutic target, particularly for high-risk PDAC patients.

Publication History

Article published online:
04 September 2025