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For the Slovenian region, see Kras.
Kirsten rat sarcoma viral oncogene homolog
PDB 1d8d EBI.jpg
Rendering of 1D8D
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM190070 MGI96680 HomoloGene37990 GeneCards: KRAS Gene
RNA expression pattern
PBB GE KRAS 204009 s at tn.png
PBB GE KRAS 204010 s at tn.png
PBB GE KRAS 214352 s at tn.png
More reference expression data
Species Human Mouse
Entrez 3845 16653
Ensembl ENSG00000133703 ENSMUSG00000030265
UniProt P01116 P32883
RefSeq (mRNA) NM_004985 NM_021284
RefSeq (protein) NP_004976 NP_067259
Location (UCSC) Chr 12:
25.2 – 25.25 Mb
Chr 6:
145.22 – 145.25 Mb
PubMed search [1] [2]

GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene.[1][2]

The protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.[3] Like other members of the ras subfamily, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprene group on its C-terminus. There are two protein products of the KRAS gene in mammalian cells that result from the use of alternative exon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B, these proteins have different structure in their C-terminal region and utilise different mechanisms to localize to cellular membranes including plasma membrane.[4]


KRAS acts as a molecular on/off switch. Once it is turned on, it recruits and activates proteins necessary for the propagation of growth factor and other receptors' signal such as c-Raf and PI 3-kinase. KRAS upregulates the GLUT1 glucose transporter, thereby contributing to the Warburg effect in cancer cells.[5] KRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide converting it to GDP. Upon conversion of GTP to GDP, KRAS is turned off. The rate of conversion is usually slow but can be sped up dramatically by an accessory protein of the GTPase-activating protein (GAP) class, for example RasGAP. In turn KRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example SOS1, which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in the cytosol and the GEF is released from ras-GTP.

Other members of the Ras family include: HRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.

Clinical significance[edit]

This proto-oncogene is a Kirsten ras oncogene homolog from the mammalian ras gene family. A single amino acid substitution, and in particular a single nucleotide substitution, is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma.

Several germline KRAS mutations have been found to be associated with Noonan syndrome[6] and cardio-facio-cutaneous syndrome.[7]

Somatic KRAS mutations are found at high rates in leukemias, colon cancer,[8] pancreatic cancer[9] and lung cancer.[10]

Colorectal cancer[edit]

The chronological order of mutations is important in the impact of KRAS mutations in regard to colorectal cancer, with a primary KRAS mutation generally leading to a self-limiting hyperplastic or borderline lesion, but if occurring after a previous APC mutation it often progresses to cancer.[11] KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.[12][13]

KRAS mutation is predictive of a very poor response to panitumumab (Vectibix®) and cetuximab (Erbitux®) therapy in colorectal cancer.[14] Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%-50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab.[15]

Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies[16][17] have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in 2009, patients with the wild-type KRAS gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated with chemotherapy alone. Patients with the KRAS wild-type gene also showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone.[17]

Emergence of KRAS mutations is a frequent driver of acquired resistance to cetuximab anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression. It suggests to perform an early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.[18]

KRAS amplification[edit]

KRAS gene can also be amplified in colorectal cancer. KRAS amplification is mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to EGFR inhibitors. Although KRAS amplification is an infrequent event in colorectal cancer, it might be responsible for precluding response to anti-EGFR treatment in some patients.[19] Amplification of wild-type Kras has also been observed in ovarian,[20] gastric, uterine, and lung cancers.[21]

Lung cancer[edit]

Whether a patient is positive or negative for a mutation in the epidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such as erlotinib (Tarceva) or gefitinib (Iressa). Patients who harbor an EGFR mutation have a 60% response rate to erlotinib. However, the mutation of KRAS and EGFR are generally mutually exclusive.[22][23][24] Lung cancer patients who are positive for KRAS mutation (and the EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less.[22]

KRAS Testing[edit]

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.[25]

In 2012, the FDA also cleared QIAGEN’s therascreen KRAS test, which is a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to aid physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue indicates that the patient may not benefit from treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.[26]


KRAS has been shown to interact with:


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Further reading[edit]

  • Kahn S, Yamamoto F, Almoguera C, Winter E, Forrester K, Jordano J, Perucho M (1987). "The c-K-ras gene and human cancer (review)". Anticancer Res. 7 (4A): 639–52. PMID 3310850. 
  • Yamamoto F, Nakano H, Neville C, Perucho M (1985). "Structure and mechanisms of activation of c-K-ras oncogenes in human lung cancer". Prog. Med. Virol. 32: 101–14. PMID 3895297. 
  • Porta M, Ayude D, Alguacil J, Jariod M (2003). "Exploring environmental causes of altered ras effects: fragmentation plus integration?". Mol. Carcinog. 36 (2): 45–52. doi:10.1002/mc.10093. PMID 12557259. 
  • Smakman N, Borel Rinkes IH, Voest EE, Kranenburg O (2005). "Control of colorectal metastasis formation by K-Ras". Biochim. Biophys. Acta 1756 (2): 103–14. doi:10.1016/j.bbcan.2005.07.001. PMID 16098678. 
  • Castagnola P, Giaretti W (2005). "Mutant KRAS, chromosomal instability and prognosis in colorectal cancer". Biochim. Biophys. Acta 1756 (2): 115–25. doi:10.1016/j.bbcan.2005.06.003. PMID 16112461. 
  • Deramaudt T, Rustgi AK (2005). "Mutant KRAS in the initiation of pancreatic cancer". Biochim. Biophys. Acta 1756 (2): 97–101. doi:10.1016/j.bbcan.2005.08.003. PMID 16169155. 
  • Pretlow TP, Pretlow TG (2005). "Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer?". Biochim. Biophys. Acta 1756 (2): 83–96. doi:10.1016/j.bbcan.2005.06.002. PMID 16219426. 
  • Su YH, Wang M, Aiamkitsumrit B, Brenner DE, Block TM (2005). "Detection of a K-ras mutation in urine of patients with colorectal cancer". Cancer Biomark 1 (2-3): 177–82. PMID 17192038. 
  • Domagała P, Hybiak J, Sulżyc-Bielicka V, Cybulski C, Ryś J, Domagała W (2012). "KRAS mutation testing in colorectal cancer as an example of the pathologist's role in personalized targeted therapy: a practical approach". Pol J Pathol 63 (3): 145–64. doi:10.5114/PJP.2012.31499. PMID 23161231. 

External links[edit]