GTPase HRas and GTPase NRas (HRAS and NRAS)

Mutant HRAS and NRAS variants are oncogenic forms of the small GTPase proteins HRas and NRas, which serve as critical molecular switches in cellular signaling. These proteins cycle between an active GTP-bound state and an inactive GDP-bound state to regulate pathways such as MAPK/ERK and PI3K/AKT, which are essential for cell growth, differentiation, and survival [1.3.2, 1.3.5]. Activating somatic mutations, most commonly at codons 12, 13, or 61, impair the intrinsic GTPase activity or increase nucleotide exchange, locking the proteins in a constitutively active state that drives malignant transformation [1.3.3, 1.5.2]. HRAS mutations are frequently identified in head and neck squamous cell carcinoma (HNSCC), bladder cancer, and salivary gland tumors, while NRAS mutations are a hallmark of melanoma and certain hematologic malignancies like acute myeloid leukemia [1.1.2, 1.3.4, 1.4.4]. Historically considered undruggable due to their high affinity for GTP and lack of deep binding pockets, these targets are now being successfully addressed with isoform-specific strategies, such as farnesyltransferase inhibitors (e.g., tipifarnib) for HRAS and MEK inhibitors or novel pan-RAS inhibitors for NRAS [1.4.2, 1.5.1]. Clinical management often involves genomic profiling to identify specific variants and allele frequencies to guide the use of targeted therapies and predict resistance to EGFR inhibitors [1.2.3, 1.2.5].

Other names

Harvey rat sarcoma viral oncogene homologNeuroblastoma RAS viral oncogene homologH-RasN-Rasp21rasTransforming protein p21

Farnesyltransferase inhibition, MEK inhibition, pan-RAS inhibition, ERK inhibition, GTPase activity modulation