S100A2 and the Np63 Network, an overlooked pancreatic cancer drug target

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an abysmal ~10% survival rate at 5-years. With 48,000 projected deaths in 2021 it is now the third most common cause of cancer death in the USA, and will be number two by 2030. In Australia (2020) there were 3,900 new cases and a staggering 3,300 deaths. Current therapies are palliative at best highlighting the urgent need for novel therapeutic agents targeting molecular phenotypes not responsive to current treatments. The highly heterogeneic and metastatic nature of PDAC presents a major challenge in therapeutic development. Recent integratomic studies have demonstrated that PDAC is composed of two major transcriptomic subtypes - classical (pancreatic) and squamous (or quasi-mesenchymal/basal-like), which are characterised by distinct mutational landscapes. The squamous subtype is associated with gene silencing of endoderm specification genes; metabolic reprogramming; and an extremely poor clinical outcome. The squamous subtype shows significant S100A2 upregulation, and its presence is associated with poor patient prognosis. This has been overlooked in the pancreatic cancer drug development pipeline and offers an unparalleled opportunity to specifically target biomarkers known to be upregulated in PDAC. Importantly, S100A2 is considered a validated PDAC biomarker. We have identified molecular mechanisms that contribute to these aggressive, metastatic subtypes, and are targetable with novel drugs.