Kirsten rat sarcoma virus oncogene homolog (KRAS), Neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey rat sarcoma virus oncogene homolog (HRAS) mutants (RAS mutants)

The RAS GTPase family, comprising KRAS (Kirsten rat sarcoma virus oncogene homolog), NRAS (Neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey rat sarcoma virus oncogene homolog), functions as a set of molecular switches that regulate signal transduction pathways controlling cell growth and survival (UniProt P01116, P01111, P01112). Mutations in these proteins, particularly at codons 12, 13, and 61, lock them in a constitutively active GTP-bound state, driving uncontrolled oncogenic signaling through the MAPK and PI3K pathways (PubMed: 33009116). While early drug discovery focused on specific alleles like KRAS G12C, recent advancements have targeted a broader spectrum of mutations, including G12D, G12V, and G12R, which are prevalent in pancreatic, colorectal, and lung cancers (Nature, 2023). These pan-RAS or multi-mutant inhibitors often utilize novel mechanisms such as molecular glues that bind the active ON state of the protein in complex with chaperones like Cyclophilin A (Revolution Medicines, 2024). Targeting the multi-mutant spectrum aims to address the high unmet need in patients whose tumors harbor non-G12C mutations or who develop resistance to allele-specific inhibitors. Clinical development of these agents requires careful monitoring of safety profiles due to the fundamental role of RAS signaling in normal cellular homeostasis.

Other names

Pan-RASKRAS/NRAS/HRAS oncogenic variantsp21 RASRAS multi-mutant spectrumRAS GTPase family mutants

Inhibition of oncogenic signaling by binding to the active (GTP-bound) or inactive (GDP-bound) states of RAS mutants, often utilizing molecular glues to form tri-complexes with chaperones like Cyclophilin A to sterically block effector interactions (Nature, 2023; Revolution Medicines, 2024).