An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

SIMPLE SUMMARY: Pancreatic cancer refers to a group of malignancies of which pancreatic ductal adenocarcinoma (PDAC) is the most common form. It is an aggressive tumour with few treatment options and very poor outcomes. There is an unmet need for novel targeted therapies for PDAC. In this regard, a better understanding of PDAC biology and in particular new pathways that contribute to disease progression would help identify novel targets for therapeutic intervention. Growing evidence implicates the unfolded protein response (UPR) in many cancers, and this article explores the evidence that supports a role for the UPR in PDAC. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.