KRAS (K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signaling. When functioning normally, it controls cell proliferation. When mutated, the negative signal is disturbed. Thus, cells can continue proliferating, and often develop into cancer.
Called KRAS because it was first identified as oncogen in Kirsten RAt Sarcoma virus. Virus oncogenes are from the cellular genome. Thus, the KRAS gene in the cellular genome is called a proto-oncogen.
The gene product was first discovered as p21 GTPase. Like other members of the racial subfamily, the KRAS protein is GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to the cell membrane because of the isoprene group in C-terminus. There are two protein products of the KRAS gene in mammalian cells resulting from the use of alternative exon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B, these proteins have different structures in the C-terminal region and their use. Different mechanisms for localizing cell membranes include plasma membranes.
Video KRAS
Function
KRAS acts as a switch on/off molecule, using protein dynamics. Once allosterically activated, it recruits and activates the proteins necessary for the spread of growth factors, as well as other cell signal receptors such as c-Raf and PI 3-kinase. KRAS enhances GLUT1 glucose transport regulation, thus contributing to the Warburg effect on cancer cells. KRAS binds GTP in its active state. It also has intrinsic enzymatic activity that cuts the nucleotide terminal phosphate, turning it into GDP. After converting GTP to GDP, KRAS is disabled. Conversion rates are usually slow, but can be dramatically increased by the GTPase-activating protein (GAP) class accessory protein, eg RasGAP. In turn, KRAS can bind to the Guanine Nucleotide Exchange Factor (GEF) protein class (such as SOS1), which forces the release of bound nucleotides (GDP). Furthermore, KRAS binds GTP in the cytosol and GEF is released from the GTP-races.
Other members of the Ras family include: HRAS and NRAS. All of these proteins are arranged in the same way and look different on their action sites inside the cell.
Maps KRAS
Clinical interests
These proto-oncogenes are homologous oncogenes of Kirsten race from the mammalian race gene family. The substitution of a single amino acid, and in particular a single nucleotide substitution, is responsible for activation mutations. The resulting transformation proteins are involved in various malignancies, including pulmonary adenocarcinoma, mucinous adenoma, pancreatic ductal carcinoma and colorectal cancer.
Several mutations of KRAS germline have been found to be associated with Noonan syndrome and cardio-facio-cutaneous syndrome.
Somatik KRAS mutations are found at high levels in leukemia, colorectal cancer, pancreatic cancer and lung cancer.
Colorectal cancer
The impact of the KRAS mutation depends heavily on the sequence of mutations. Primary KRAS mutations generally lead to hyperplastic lesions or self-limiting limits, but if they occur after previous APC mutations often develop into cancer. KRAS mutations are more frequently observed in cecal cancers than colorectal cancers located elsewhere from the rising colon to the rectum.
KRAS mutations are predictive of very poor response to panitumumab (VectibixÃ,®) and cetuximab (ErbituxÃ,®) therapy in colorectal cancer. Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR inhibitors is to test certain "activate" mutations in a gene encoding KRAS, occurring in 30% -50% of colorectal cancers.. Studies show patients whose tumors express a mutated version of the KRAS gene will not respond to cetuximab or panitumumab.
Although the presence of wild (or normal) KRAS genes does not guarantee that these drugs will work, a number of large studies have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild type tumors. In the CRYSTAL Phase III 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 with those treated with chemotherapy alone. Patients with the KRAS wild-type gene also showed a 32% reduced risk of developing disease compared with patients receiving chemotherapy alone.
The emergence of KRAS mutations is often the resistance driver obtained for anti-EGFR cetuximab therapy in colorectal cancer. The emergence of KRAS mutant clones can be detected in non-invasive months before the development of radiographs. This suggests to initiate an early MEK inhibitor as a rational strategy to delay or reverse drug resistance.
KRAS Amplification
The KRAS gene can also be reinforced in colorectal cancer. KRAS Amplification is mutually exclusive with KRAS mutations. Tumors or cell lines that store these genetic lesions are unresponsive to EGFR inhibitors. Although KRAS amplification is a rare occurrence of colorectal cancer, it may be responsible for blocking response to anti-EGFR treatment in some patients. Amplification of wild-type Kras has also been observed in ovarian, stomach, uterine, and lung cancers.
Lung cancer
Whether a patient is positive or negative for mutations in epidermal growth factor receptors (EGFR) will predict how patients will respond to certain EGFR antagonists such as erlotinib (Tarceva) or gefitinib (Iressa). Patients with EGFR mutations had a 60% response rate to erlotinib. However, KRAS and EGFR mutations are generally mutually exclusive. Positive lung cancer patients for KRAS mutations (and EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less.
Different types of data including mutation status and gene expression have no significant prognostic strength. No correlation to survival was observed in 72% of all studies with KRAS sequencing performed on non-small cell lung cancer (NSCLC). However, the KRAS mutation can not only affect the gene itself and the appropriate protein expression, but it can also affect the expression of other downstream genes involved in important pathways that regulate cell growth, differentiation and apoptosis. Different expressions of these genes in KRAS mutant tumors may have a more prominent role in influencing patient clinical outcomes.
A 2008 paper published in Cancer Research concluded that the in vivo administration of the oncrasin-1 compound suppressed the growth of xenografts xenografts human-mutant K-ras by 70% and prolonged the nude survival of rats carrying this tumor, without causing detectable toxicity ", and that" the results show that active oncrasin-1 or analogue could be a new class of anticancer agents that effectively kill K-Ras mutant cancer cells. "
KRAS test
In July 2009, the US Food and Drug Administration (FDA) updated the label of two anti-EGFR monoclonal antibodies (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for the treatment of metastatic colorectal cancer to include information about KRAS mutations.
In 2012, the FDA also cleans the QIAGEN therascreen ACAS 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 assist physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue suggests that patients may not benefit from treatment with Erbitux. If the test results show that the KRAS mutation does not exist in colorectal cancer cells, then the patient may be considered for treatment with Erbitux.
Interactions
KRAS has been proven to interact with:
- C-Raf,
- PIK3CG,
- RALGDS, and
- RASSF2.
- Calmodulin
References
Further reading
External links
- KRAS Reference Standard - Learn more about KRAS Reference Control
- GeneReviews/NCBI/NIH/UW is included in Cardiofaciocutaneous Syndrome
- GeneReviews/NCBI/NIH/UW entered in Noonan syndrome
- KRAS2 protein, man at US National Library of Medicine Subject Medical Headings (MeSH)
Source of the article : Wikipedia
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