Kirsten rat sarcoma viral oncogene homolog protein (KRAS)

The **Kirsten rat sarcoma viral oncogene homolog protein** (**KRAS**) is a small **GTPase enzyme** belonging to the Ras family. It acts as a molecular switch within cells by cycling between active (GTP-bound) and inactive (GDP-bound) states. When activated by extracellular signals—often through receptor tyrosine kinases like EGFR—KRAS relays signals that regulate cell growth, division, differentiation, and survival. Mutations that constitutively activate this protein drive uncontrolled cellular proliferation and are among the most common genetic alterations found across human cancers—including lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal carcinoma. These mutations typically occur at codons encoding glycine residues at positions 12 or 13 or glutamine at position 61. Because mutated forms lead directly to oncogenesis ("driver" mutations), **KRAS** has long been considered a high-value but difficult therapeutic target ("undruggable"). Only recently have drugs specifically inhibiting certain mutant forms—such as sotorasib and adagrasib for the *G12C* variant—been approved. The presence of activating *KRAS* mutations also serves as an important biomarker guiding treatment decisions; notably predicting lack of benefit from anti-EGFR monoclonal antibodies in metastatic colorectal cancer. Beyond its role in malignancy, germline *KRAS* mutations can cause developmental syndromes such as Noonan syndrome and cardio-facio-cutaneous syndrome due to dysregulated signaling during embryogenesis.

Other names

K-RasKi-Rasc-K-rasc-Ki-rasKRAS1KRAS2

Covalent inhibition of mutant K-Ras protein at the cysteine residue in the G12C variant, locking it in an inactive GDP-bound state and preventing downstream signaling that drives tumor growth. Indirect targeting via upstream or downstream pathway inhibition (e.g., MEK inhibitors), though these are not specific to KRAS itself.