RAS is one of the most important molecules in the EGFR downstream signaling pathway . Three human RAS genes have been identified: HRAS, KRAS, and NRAS. They are small GTP-GDP–binding proteins that act as functional switches by coupling growth factor receptors to intracellular signaling pathways. RAS can activate the kinase RAF, the mitogen-activated extracellular signal-regulated kinases (ERK)1 and ERK2, PI3K, and many other proteins to promote cell proliferation. Because activation of the EGFR leads to activation of the intracellular effector KRAS, it was hypothesized that mutations in the KRAS coding gene could lead to a constitutively activated KRAS protein that is independent from upstream signals, which subsequently could affect clinical response to EGFR inhibitors. Mutations in the KRAS proto-oncogene occur in approximately 35 to 40% of colon cancer, are single nucleotide point mutations mostly in codons 12 and 13 of exon 2, and are early events during the development of colon cancer carcinogenesis. The incidence of KRAS mutations is identical throughout all stages, and a very high concordance has been reported between paired primary cancers and metastatic samples. There is no complete agreement on the prognostic role of KRAS mutations. The central role K-, H- and N-Ras play in regulating diverse cellular pathways important for cell growth, differentiation and survival is well established. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors. Of the Ras proteins, K-ras is the most frequently mutated and is therefore an attractive target for cancer therapy. The complexity of K-ras signaling presents many opportunities for therapeutic targeting. A number of different approaches aimed at abrogating K-ras activity have been explored in clinical trials.
Drug targets for cancer: KRAS research reagents
Other vital drug targets for cancer likeKRAS:
Prenen H, Tejpar S, Van Cutsem E. New strategies for treatment of KRAS mutant metastatic colorectal cancer[J]. Clinical Cancer Research, 2010, 16(11): 2921-2926.