KRAS proto-oncogene GTPase G12C mutant (KRAS G12C)

KRAS G12C is a specific mutation of the KRAS protein where glycine at position 12 is replaced by cysteine. The KRAS protein normally functions as a molecular switch in the RAS/MAPK pathway, converting between active (GTP-bound) and inactive (GDP-bound) states to regulate cell growth, proliferation, and differentiation. The G12C mutation impairs GTPase function and decreases the conversion from active to inactive KRAS, resulting in increased downstream signaling that drives uncontrolled cell proliferation. This mutation locks the protein in an active GTP-bound form, leading to constitutive activation of downstream pathways that promote cancer development. KRAS G12C has distinct biological properties compared to other KRAS mutations. It shows higher RAL signaling and lower phosphorylated AKT compared to wild-type or other KRAS mutations. While it is resistant to canonical GAP-induced GTP hydrolysis, it retains intrinsic GTPase activity and is sensitive to non-canonical GAP-induced hydrolysis, which has been exploited for therapeutic targeting. The development of covalent inhibitors that specifically target the cysteine residue in KRAS G12C represents a significant breakthrough in cancer treatment, as KRAS mutations were previously considered "undruggable". These inhibitors have shown promising results in clinical trials and offer new hope for patients with KRAS G12C-mutant cancers.

Other names

Kirsten rat sarcoma virus G12C mutantK-Ras G12C

Covalent binding to the mutant cysteine residue in GDP-bound KRAS G12C, locking the G12C-mutated KRAS protein in a non-activated GDP-binding state, irreversibly inhibiting the proliferative activity of tumor cells, and inhibiting GTP-loading and downstream KRAS-dependent signaling.