Kirsten rat sarcoma virus proto-oncogene GTPase G13C mutant (KRAS G13C) (KRAS G13C)

KRAS G13C is a specific oncogenic variant of the Kirsten rat sarcoma virus proto-oncogene (KRAS), a small GTPase that functions as a molecular switch in cell signaling pathways. This mutation involves a missense substitution where glycine at position 13 is replaced by cysteine, which disrupts the protein's intrinsic GTPase activity and renders it insensitive to GTPase-activating proteins (GAPs) (nih.gov, 2024). Consequently, the protein remains locked in a constitutively active, GTP-bound state, leading to the persistent activation of downstream signaling cascades such as the MAPK/ERK and PI3K/AKT pathways (elifesciences.org, 2023). These pathways drive the uncontrolled cell proliferation, survival, and metabolic reprogramming characteristic of malignant transformation. KRAS G13C is a significant driver in several cancers, most notably colorectal cancer and non-small cell lung cancer (NSCLC), where it is associated with poor prognosis and resistance to standard therapies (patsnap.com, 2024). Therapeutic targeting of KRAS G13C has evolved from being considered "undruggable" to the development of direct allele-specific and multi-RAS inhibitors. Current strategies include covalent inhibitors that specifically target the mutant cysteine residue at codon 13 and non-covalent RAS(ON) inhibitors that bind the active, GTP-bound form of the protein (ascopost.com, 2026). Additionally, indirect approaches such as SOS1 inhibition are being explored to prevent the nucleotide exchange required for KRAS activation (nih.gov, 2025). Clinical challenges in targeting this molecule include the management of class-related toxicities, such as gastrointestinal distress and skin reactions, as well as the emergence of secondary resistance mutations that bypass the inhibited pathway (intellectia.ai, 2026).

Other names

KRAS p.G13CKirsten rat sarcoma viral oncogene homolog G13CKRAS codon 13 cysteine mutationKRAS G13C mutant protein

Covalent inhibition of the mutant cysteine residue, non-covalent inhibition of the active GTP-bound (ON) state, and inhibition of SOS1-mediated nucleotide exchange.