GTPase HRas (HRAS)

HRAS G12C refers to a specific oncogenic mutant form of the HRas proto-oncogene, a member of the RAS family of small GTPases. Under physiological conditions, HRAS acts as a molecular switch, cycling between an active GTP-bound state and an inactive GDP-bound state to regulate signaling pathways such as MAPK/ERK and PI3K/AKT, which are critical for cell growth, differentiation, and survival [3, 15]. The G12C mutation involves a missense substitution of glycine with cysteine at codon 12, which impairs the protein's intrinsic GTPase activity and its response to GTPase-activating proteins (GAPs), resulting in a constitutively active oncoprotein [5, 16]. While HRAS mutations are less frequent than KRAS mutations, the G12C variant is a recognized driver in specific malignancies, including head and neck squamous cell carcinoma and bladder cancer [5, 12]. Therapeutic targeting of HRAS G12C has been advanced by the development of covalent inhibitors, such as sotorasib and RMC-6291, which exploit the unique reactive cysteine to irreversibly lock the protein in its inactive conformation [13, 16]. Clinical management of patients with these mutations relies on genomic profiling to identify the G12C biomarker and monitoring for potential resistance mechanisms or off-target toxicities [17, 18].

Other names

HRAS1p21rasRASH1c-H-rasTransforming protein p21H-Ras proto-oncogeneGTP-binding protein HRas

Covalent inhibition of the mutant cysteine residue at position 12, which irreversibly traps the protein in its inactive GDP-bound state and prevents downstream oncogenic signaling through the MAPK and PI3K pathways.