Rat sarcoma virus GTPase (RAS) family (RAS)

The RAS protein family, comprising KRAS, HRAS, and NRAS, consists of small GTPases that act as critical molecular switches in intracellular signaling pathways (UniProt: P01112, P01111, P01116). These proteins cycle between an active GTP-bound state and an inactive GDP-bound state to regulate fundamental cellular processes such as proliferation, differentiation, and survival (PubMed: 34634254). Mutations in RAS genes are found in approximately 30% of all human cancers, making them some of the most significant oncogenic drivers, particularly in pancreatic, lung, and colorectal malignancies (Nature Reviews Drug Discovery, 2022). While early drug discovery focused on specific mutant isoforms like KRAS G12C, the Pan-RAS approach targets multiple RAS isoforms or a broad spectrum of mutations simultaneously to address a wider patient population (Revolution Medicines, 2023). This strategy is designed to prevent the bypass signaling and adaptive resistance often seen with single-isoform inhibitors. Pan-RAS inhibitors typically function by stabilizing the inactive conformation of the proteins or by preventing their interaction with downstream effectors like RAF and PI3K. A major challenge in developing these agents is achieving a therapeutic window that spares wild-type RAS function in normal cells to avoid systemic toxicity (PubMed: 35115684). Current clinical candidates, such as RMC-6236, are being evaluated for their ability to treat a wide variety of RAS-mutant solid tumors.

Other names

KRASHRASNRASp21rasTransforming protein p21Pan-RAS

Inhibition of multiple RAS isoforms (KRAS, HRAS, NRAS) in their active (GTP-bound) or inactive (GDP-bound) states to disrupt downstream oncogenic signaling through the MAPK and PI3K pathways (Nature Reviews Drug Discovery, 2022).