Rat sarcoma virus oncogene homolog (RAS)

The Ras protein family, comprising KRAS, HRAS, and NRAS, consists of small GTPases that act as critical molecular switches in cellular signaling pathways, including the MAPK/ERK and PI3K/AKT/mTOR cascades [1, 2]. These proteins cycle between an active GTP-bound state and an inactive GDP-bound state to regulate fundamental processes such as cell growth, differentiation, and survival [1, 4]. Mutations in Ras genes are found in approximately 30% of all human cancers, with KRAS being the most frequently mutated isoform, particularly in pancreatic, colorectal, and lung adenocarcinomas [2, 4]. Oncogenic mutations typically impair the intrinsic GTPase activity or GAP-mediated GTP hydrolysis, leading to constitutive activation and uncontrolled cell proliferation [1, 2]. While long considered 'undruggable,' the development of allele-specific covalent inhibitors like sotorasib and adagrasib has successfully targeted the KRAS G12C mutation by binding to a cryptic pocket in the inactive state [3, 4]. Furthermore, therapeutic strategies such as oncolytic viruses (e.g., Pelareorep) exploit the specific signaling environment of Ras-activated tumor cells to achieve selective viral replication and cell death [5].

Other names

KRASHRASNRASp21 RasTransforming protein p21Ras GTPase

Drugs targeting Ras proteins primarily function through allele-specific covalent inhibition (e.g., sotorasib targeting KRAS G12C), which locks the protein in its inactive GDP-bound state and prevents downstream signaling through the MAPK and PI3K pathways [3, 4]. Other approaches include oncolytic viruses like pelareorep, which selectively replicate in and lyse cells with activated Ras signaling by exploiting the impaired antiviral response in these cells [5]. Additionally, farnesyltransferase inhibitors like tipifarnib prevent the post-translational modification required for Ras membrane localization and activity [4].