KRASmutant

KRASmutant refers to tumors in which the KRAS gene carries activating mutations that drive cancer development and progression. The most common substitutions occur at codons 12 and 13 (for example, G12C, G12D, G13D) and at codon 61, leading to sustained KRAS signaling.

KRAS encodes a small GTPase that toggles between inactive GDP-bound and active GTP-bound states. Mutations reduce intrinsic GTPase activity or promote nucleotide exchange, locking KRAS in an active form and promoting downstream pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR. This constitutive signaling supports cell proliferation, survival, and oncogenesis.

KRAS mutations are among the most frequent oncogenic alterations across several solid tumors. Pancreatic ductal adenocarcinoma has among the highest prevalence, with roughly most cases harboring KRAS mutations. Colorectal cancer shows mutations in about 40%, and lung adenocarcinoma around 25%. In clinical practice, KRAS mutation status is an important biomarker: in colorectal cancer, the presence of KRAS mutations predicts lack of response to anti-EGFR monoclonal antibodies, guiding therapy choices; in lung cancer, KRAS status influences prognosis and treatment options, particularly with emerging targeted therapies.

Therapeutically, KRAS was long considered undruggable, but selective inhibitors targeting the G12C mutation have changed the landscape. Sotorasib (AMG 510) and adagrasib (KRAZATI) have received approval for KRAS G12C-mutant non-small cell lung cancer, with ongoing evaluation in other cancers and in combination regimens. Non-G12C KRAS mutations remain more challenging to target, prompting ongoing research into upstream/downstream approaches and combination strategies.

Molecular testing using targeted sequencing or next-generation sequencing is used to identify KRAS mutations and determine the specific subtype, informing prognosis and eligibility for targeted therapies.