KRAS 2A Human

The Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is one of the most frequently mutated oncogenes in human cancers. It plays a critical role in the regulation of cell division, and its mutations are often associated with various types of cancer, including non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC) .

KRAS was first identified in rats in the 1980s and belongs to the RAS gene family, which also includes HRAS and NRAS . The KRAS protein is a GTPase that primarily binds to guanosine diphosphate (GDP) and is in an inactive conformation maintained by intrinsic guanosine triphosphate (GTP) hydrolytic activity . When GTP binds to KRAS, it shifts the active site from an open to a closed conformation, allowing multiple downstream effector pathways to interact and activate .

KRAS interacts with GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), which regulate its activity. The active state of KRAS, when bound to GTP, results in the activation of downstream signaling pathways such as the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways . These pathways are crucial for cell proliferation, differentiation, and survival.

KRAS mutations are genetic drivers in numerous cancer types and are often associated with aggressive disease and poor prognosis . For many years, KRAS was considered “undruggable” due to its high affinity for GTP and the lack of classic drug binding sites . However, recent advancements have led to the development of allele-specific covalent inhibitors, such as AMG510 (sotorasib), which have shown marked clinical responses across multiple tumor types .

The advent of KRAS (G12C) inhibitors has made KRAS mutations druggable . Despite the remarkable clinical responses, resistance to monotherapy of KRAS inhibitors eventually develops . Researchers are exploring combination therapies and other strategies to overcome this resistance and improve treatment outcomes .