Mechanisms of Cancer Cell Death: Therapeutic Implications for Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic cancer is a disease which is known to be highly deadly, with only 8% of people diagnosed surviving for more than 5 years. Multiple factors contribute to this poor survival rate, including a lack of early symptoms leading to late diagnosis and a high tendency for the cancer to rapidly spread throughout the body. Although there has been a lot of work in this area, we still lack an effective cure for pancreatic cancer. In this review, we aim to outline the latest research on possible treatments, including those which disrupt signalling pathways in the cell, disturb the cancers’ fuel sources, overload cancer cells with mutations, and re-direct the body’s immune system to attack the tumour. We also look at how we could eliminate a particularly aggressive group of cells within the tumour (‘cancer stem cells’) which are thought to be important to pancreatic cancer growth and spread. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer that is strongly associated with poor prognosis and short median survival times. In stark contrast to the progress seen in other cancer types in recent decades, discoveries of new treatments in PDAC have been few and far between and there has been little improvement in overall survival (OS). The difficulty in treating this disease is multifactorial, contributed to by late presentation, difficult access to primary tumour sites, an ‘immunologically cold’ phenotype, and a strong tendency of recurrence likely driven by cancer stem cell (CSC) populations. Furthermore, apparently contrasting roles of tumour components (such as fibrotic stroma) and intracellular pathways (such as autophagy and TGFβ) have made it difficult to distinguish beneficial from detrimental drug targets. Despite this, progress has been made in the field, including the determination of mFOLFIRINOX as the standard-of-care adjuvant therapy and the discovery of KRAS(G12C) mutant inhibitors. Moreover, new research, as outlined in this review, has highlighted promising new approaches including the targeting of the tumour microenvironment, enhancement of immunotherapies, epigenetic modulation, and destruction of CSCs.