Ras proteins (RAS)

Ras proteins (KRAS, HRAS, and NRAS) are small GTPases that function as essential molecular switches in cellular signal transduction [1, 6]. They cycle between an inactive GDP-bound state and an active GTP-bound state, a process regulated by guanine nucleotide exchange factors (GEFs) like SOS1 and GTPase-activating proteins (GAPs) [1, 10]. Once activated, Ras proteins form signaling complexes with various downstream effectors, most notably RAF kinases and PI3K, to initiate cascades such as the MAPK/ERK and PI3K/AKT/mTOR pathways [7, 12]. These pathways are critical for regulating fundamental cellular processes, including proliferation, differentiation, and survival [5, 12]. Mutations in Ras genes are among the most frequent drivers of human malignancy, occurring in approximately 30% of all cancers, with particularly high prevalence in pancreatic, colorectal, and lung adenocarcinomas [3, 6]. Historically considered "undruggable" due to their high affinity for GTP and lack of traditional binding pockets, recent breakthroughs have led to the approval of covalent inhibitors like sotorasib and adagrasib that specifically target the KRAS G12C mutation [3, 11]. Beyond oncology, germline mutations in the Ras pathway cause a group of developmental disorders known as RASopathies, including Noonan syndrome and Costello syndrome [1, 9]. Therapeutic strategies now include direct Ras inhibition, disruption of Ras-effector interactions, and targeting of downstream signaling components [2, 6].

Other names

p21 RasRas GTPaseKirsten rat sarcoma viral oncogene homologHarvey rat sarcoma viral oncogene homologNeuroblastoma RAS viral oncogene homologRas superfamily

Covalent inhibition of the inactive GDP-bound state (e.g., KRAS G12C), inhibition of farnesyltransferase to prevent membrane localization, and inhibition of downstream effector pathways such as RAF/MEK/ERK and PI3K/AKT.