Targeting KRAS in PDAC: A New Way to Cure It?

SIMPLE SUMMARY: Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory and poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. KRAS is the most commonly mutated oncogene in PDAC. It has been considered the “untargetable” oncogene for decades until the emergence of G12C inhibitors, which put an end to this dilemma by covalent binding to the switch-II pocket of the G12C mutant protein. However, G12C inhibitors showed remarkable efficacy against non-small-cell lung cancer (NSCLC), while the G12C mutation is rare in PDAC. Based on the successful experience of G12C inhibitors, targeting KRAS G12D/V, which forms the majority of KRAS mutations in PDAC, is gradually being regarded as a potential therapy. ABSTRACT: Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being “undruggable” due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRAS(G12C) inhibitors; the covalent inhibitors bond to the switch-II pocket of the KRAS(G12C) protein. The KRAS(G12C) inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRAS(G12C)-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRAS(G12D/V) inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRAS(G12D/V) and discuss the potential applications.