KRAS

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

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 is_associated_with::cancers. Like other members of the Ras family, the KRAS protein is a is_associated_with::GTPase and is an early player in many is_associated_with::signal transduction pathways. KRAS is usually tethered to is_associated_with::cell membranes because of the presence of an is_associated_with::isoprenyl group on its is_associated_with::C-terminus.

Function
KRAS acts as a molecular on/off switch. Once it is turned on, it recruits and activates proteins necessary for the propagation of is_associated_with::growth factor and other receptors' signal such as is_associated_with::c-Raf and is_associated_with::PI 3-kinase. 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 is_associated_with::GTPase-activating protein (GAP) class, for example is_associated_with::RasGAP. In turn KRAS can bind to proteins of the is_associated_with::Guanine Nucleotide Exchange Factor (GEF) class, for example is_associated_with::SOS1, which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in the is_associated_with::cytosol and the GEF is released from ras-GTP.

Other members of the Ras family include: is_associated_with::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
This is_associated_with::proto-oncogene is a Kirsten ras is_associated_with::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 is_associated_with::lung adenocarcinoma, is_associated_with::mucinous adenoma, is_associated_with::ductal carcinoma of the is_associated_with::pancreas and is_associated_with::colorectal carcinoma.

Several is_associated_with::germline KRAS mutations have been found to be associated with is_associated_with::Noonan syndrome and is_associated_with::cardio-facio-cutaneous syndrome.

Somatic KRAS mutations are found at high rates in is_associated_with::leukemias, is_associated_with::colon cancer, is_associated_with::pancreatic cancer and is_associated_with::lung cancer.

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

KRAS mutation is predictive of a very poor response to is_associated_with::panitumumab (Vectibix®) and is_associated_with::cetuximab (Erbitux®) therapy in colorectal cancer. 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.

Although presence of the wild-type (or normal) KRAS gene 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 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.

Emergence of KRAS mutations is a frequent driver of acquired resistance to is_associated_with::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 is_associated_with::MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

KRAS amplification
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 is_associated_with::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. Amplification of wild-type Kras has also been observed in ovarian, gastric, uterine, and lung cancers.

Lung cancer
Whether a patient is positive or negative for a mutation in the is_associated_with::epidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such as is_associated_with::erlotinib (Tarceva) or is_associated_with::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. 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.

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

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.

Interactions
KRAS has been shown to interact with:
 * is_associated_with::C-Raf,
 * is_associated_with::PIK3CG,
 * is_associated_with::RALGDS, and
 * is_associated_with::RASSF2.