Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma is one of the deadliest malignancies in humans. Despite advances in systemic therapy, prognosis still remains poor. However, recent discoveries in the main biological event in pancreatic carcinogenesis, the KRAS mutation, have broadened our understanding of pancreatic cancer and opened a window of opportunity. Indeed, inhibitors of KRAS signaling are believed to represent a major step toward more active treatments against this disease. In this review, we describe the latest findings regarding KRAS in pancreatic ductal adenocarcinoma, along with updated preclinical and clinical data on KRAS-targeted therapy. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.