v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
189 amino acids; about 22 kDa
This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. It plays a crucial role in signal transduction in many tissues.
KRAS is one of the most frequently mutated genes in a variety of tumors. Most alterations are “missense” substitutions. There are three mutation hot spots, corresponding to amino acids 12, 13 and 61.
The majority of oncogenic KRAS proteins have impaired intrinsic and GAP-mediated GTP hydrolysis and thus express constitutive GTP-bound activaty.
Somatic KRAS mutations are common in tumors of the following tissues: pancreas (more than 50% of cases), large intestine, biliary tract, small intestine, lung, endometrium, ovary…
As RAS is frequently mutated in human cancer, it has attracted significant attention as a target for anticancer therapy. Unfortunately, efforts to develop direct inhibitors of RAS have fallen short of expectations and no direct inhibitor of KRAS or NRAS has shown meaningful clinical activity to date. Alternative approaches include inhibitors of
the key downstream effectors of RAS.
KRAS mutations predict for resistance to anti-EGFR therapy (erlotinib, cetuximab, panitumumab)
References (open access):
KRAS and BRAF: drug targets and predictive biomarkers. Vakiani E, Solit DB. J Pathol. 2011 Jan;223(2):219-29.