KRAS (K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signalling. When it functions normally, it controls cell proliferation. When it is mutated, negative signalling is disrupted. Thus, cells can continuously proliferate, and often develop into cancer.

It is called KRAS because it was first identified as an oncogene in Kirsten RAt Sarcoma virus.^[5] The viral oncogene was derived from cellular genome. Thus, KRAS gene in cellular genome is called a proto-oncogene.

The gene product was first found as a p21 GTPase.^[6][7] 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 use different mechanisms to localize to cellular membranes including the plasma membrane.^[8]

KRAS acts as a molecular on/off switch, using protein dynamics. Once it is allosterically activated, it recruits and activates proteins necessary for the propagation of growth factors, as well as other cell signaling receptors like c-Raf and PI 3-kinase. KRAS upregulates the GLUT1 glucose transporter, thereby contributing to the Warburg effect in cancer cells.^[9] KRAS binds to GTP in its active state. It also 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 deactivated. The rate of conversion is usually slow, but can be increased 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 (such as 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 in their sites of action within the cell.

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,^[10] mucinous adenoma, ductal carcinoma of the pancreas and colorectal cancer.^[11][12]

Several germline KRAS mutations have been found to be associated with Noonan syndrome^[13] and cardio-facio-cutaneous syndrome.^[14]

Somatic KRAS mutations are found at high rates in leukemias, colorectal cancer,^[15] pancreatic cancer^[16] and lung cancer.^[17]

The impact of KRAS mutations is heavily dependent on the order of mutations. Primary KRAS mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previous APC mutation it often progresses to cancer.^[18] KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.^[19][20]

KRAS mutation is predictive of a very poor response to panitumumab (Vectibix) and cetuximab (Erbitux) therapy in colorectal cancer.^[21]

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.^[22]

Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies^[23][24] 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.^[24]

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.^[25]

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.^[26] Amplification of wild-type Kras has also been observed in ovarian,^[27] gastric, uterine, and lung cancers.^[28]

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.^[29][30][31] 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.^[29]

Different types of data including mutation status and gene expression did not have a significant prognostic power.^[32] No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC).^[32] However, KRAS mutations can not only affect the gene itself and the expression of the corresponding protein, but can also influence the expression of other downstream genes involved in crucial pathways regulating cell growth, differentiation and apoptosis. The different expression of these genes in KRAS-mutant tumors might have a more prominent role in affecting patient’s clinical outcomes.^[32]

A 2008 paper published in Cancer Research concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity", and that the "results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents which effectively kill K-Ras mutant cancer cells."^[33]

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs indicated for treatment of metastatic colorectal cancer, panitumumab (Vectibix) and cetuximab (Erbitux), to include information about KRAS mutations.^[34]

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.^[35]

Driver mutations in KRAS underlie the pathogenesis of up to 20% of human cancers.^[36] Hence KRAS is an attractive drug target, however lack of obvious binding sites has hindered pharmaceutical development.^[37] One potential drug interaction site is where GTP/GDP binds. However due to the extraordinarily high affinity of GTP/GDP for this site, it is unlikely that drug-like small molecule inhibitors could compete with GTP/GDP binding. Other than where GTP/GDP binds, there are no obvious high affinity binding sites for small molecules.^[38] One fairly frequent driver mutation is KRASG12C which is adjacent a shallow binding site. This has allowed the development of electrophilic KRAS inhibitors that can form irreversible covalent bonds with nucleophilic sulfur atom of Cys-12 and hence selectively target KRASG12C and leave wild-type KRAS untouched.^[39] Two KRASG12C mutant covalent inhibitors have reached clinical testing: AMG 510 (Amgen)^[40] and MRTX-849 (Mirati Therapeutics)^[41] while ARS-3248 (Wellspring Biosciences/Janssen) has received an investigational new drug (IND) approval to start clinical trials.^[42] An antisense oligonucleotide (ASO), AZD4785 (AstraZeneca/Ionis Therapeutics) targeting KRAS has completed a phase I study^[43] but was discontinued from further development because of insufficient knockdown of the target.^[44]

KRAS has been shown to interact with: