KRAS
Available structures PDB Ortholog search:PDBeRCSB List of PDB id codes 4WA7,1D8D,1D8E,3GFT,4DSN,4DSO,4EPR,4EPT,4EPV,4EPW,4EPX,4EPY,4L8G,4LDJ,4LPK,4LRW,4LUC,4LV6,4LYF,4LYH,4LYJ,4M1O,4M1S,4M1T,4M1W,4M1Y,4M21,4M22,4NMM,4OBE,4PZY,4PZZ,4Q01,4Q02,4Q03,4QL3,4TQ9,4TQA,4DST,4DSU,5F2E,%%s2MSC,2MSD,2MSE
Identifiers
Aliases	KRAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, KI-RAS, KRAS1, KRAS2, NS, NS3, RALD, RASK2, K-ras, KRAS proto-oncogene, GTPase, c-Ki-ras2, OES, c-Ki-ras, K-Ras 2, 'C-K-RAS, K-Ras, Kirsten RAt Sarcoma virus, Kirsten Rat Sarcoma virus
External IDs	OMIM:190070;MGI:96680;HomoloGene:37990;GeneCards:KRAS;OMA:KRAS - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p12.1 Start 25,205,246bp[1] End 25,250,936bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 G3|6 77.37 cM Start 145,162,425bp[2] End 145,195,965bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in trigeminal ganglion pylorus nipple oral cavity mucosa of sigmoid colon mucosa of pharynx cardia jejunal mucosa tail of epididymis endothelial cell Top expressed in Paneth cell left colon medullary collecting duct conjunctival fornix hair follicle ureter cumulus cell endothelial cell of lymphatic vessel left lung lobe medial ganglionic eminence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding LRR domain binding GDP binding protein-containing complex binding GTP binding GMP binding protein binding GTPase activity identical protein binding Cellular component cytoplasm cytosol membrane focal adhesion extrinsic component of cytoplasmic side of plasma membrane plasma membrane mitochondrion membrane raft Biological process visual learning negative regulation of neuron apoptotic process response to mineralocorticoid positive regulation of protein phosphorylation regulation of long-term neuronal synaptic plasticity regulation of protein stability epidermal growth factor receptor signaling pathway positive regulation of MAP kinase activity cytokine-mediated signaling pathway negative regulation of cell differentiation stimulatory C-type lectin receptor signaling pathway response to glucocorticoid MAPK cascade axon guidance Fc-epsilon receptor signaling pathway positive regulation of nitric-oxide synthase activity forebrain astrocyte development endocrine signaling positive regulation of NF-kappaB transcription factor activity homeostasis of number of cells within a tissue striated muscle cell differentiation Ras protein signal transduction epithelial tube branching involved in lung morphogenesis regulation of synaptic transmission, GABAergic actin cytoskeleton organization leukocyte migration signal transduction positive regulation of Rac protein signal transduction positive regulation of gene expression positive regulation of cell population proliferation ERBB2 signaling pathway liver development positive regulation of cellular senescence female pregnancy response to isolation stress Sources:Amigo /QuickGO
Orthologs Species Human Mouse Entrez 3845 16653 Ensembl ENSG00000133703 ENSMUSG00000030265 UniProt P01116 P32883 RefSeq (mRNA) NM_004985 NM_033360 NM_001369786 NM_001369787 NM_021284 RefSeq (protein) NP_004976 NP_203524 NP_001356715 NP_001356716 NP_004976.2 NP_067259 NP_001390169 NP_001390170 NP_001390171 NP_001390172 NP_001390173 NP_001390174 NP_001390175 Location (UCSC) Chr 12: 25.21 – 25.25 Mb Chr 6: 145.16 – 145.2 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

KRAS (Kirsten ratsarcoma virus) is a gene that provides instructions for making a protein calledK-Ras, a part of theRAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is calledKRAS because it was first identified as a viraloncogene in theKirstenRAtSarcoma virus.^[5] The oncogene identified was derived from a cellular genome, soKRAS, when found in a cellular genome, is called aproto-oncogene.

The K-Ras protein is aGTPase, a class ofenzymes which convert thenucleotideguanosine triphosphate (GTP) intoguanosine diphosphate (GDP). In this way the K-Ras protein acts like aswitch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the nucleus.

Thegene product ofKRAS, the K-Ras protein, was first found as a p21 GTPase.^[6][7] Like other members of theras subfamily of GTPases, the K-Ras protein is an early player in manysignal transduction pathways. K-Ras is usually tethered tocell membranes because of thefarnesylation of itsC-terminus. There are two protein products of theKRAS gene in mammalian cells that result from the use of alternativeexon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B. These proteins have different structures in their C-terminal region and use different mechanisms to localize to cellular membranes, including theplasma membrane.^[8]

KRAS acts as a molecular on/off switch, usingprotein dynamics. Once it isallosterically activated, it recruits and activates proteins necessary for the propagation ofgrowth factors, as well as othercell signaling receptors likec-Raf andPI 3-kinase. KRASupregulates theGLUT1 glucose transporter, thereby contributing to theWarburg effect in cancer cells.^[9] KRAS binds toGTP in its active state. It also possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, converting it toGDP. 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 theGTPase-activating protein (GAP) class, for exampleRasGAP. In turn, KRAS can bind to proteins of theGuanine Nucleotide Exchange Factor (GEF) class (such asSOS1), which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in thecytosol and the GEF is released from ras-GTP.

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

Thisproto-oncogene is a Kirsten rasoncogene 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, includinglung adenocarcinoma,^[10]mucinous adenoma,ductal carcinoma of thepancreas andcolorectal cancer.^[11][12]

Severalgermline KRAS mutations have been found to be associated withNoonan syndrome^[13] andcardio-facio-cutaneous syndrome.^[14]SomaticKRAS mutations are found at high rates inleukemias,colorectal cancer,^[15]pancreatic cancer^[16] andlung cancer.^[17]

The impact of KRAS mutations is heavily dependent on the order of mutations. PrimaryKRAS mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previousAPC 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]

As of 2006, KRAS mutation was predictive of a very poor response topanitumumab (Vectibix) andcetuximab (Erbitux) therapy in colorectal cancer.^[21]

As of 2008, the most reliable way to predict whether a colorectal cancer patient will respond to one of theEGFR-inhibiting drugs was 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 theKRAS gene will not respond to cetuximab or panitumumab.^[22]

As of 2009, 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] had shown that cetuximab had efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in 2009, patients with the wild-typeKRAS gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated withchemotherapy alone. Patients with theKRAS wild-type gene also showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone.^[24]

As of 2012, it was known that emergence of KRAS mutations was a frequent driver of acquired resistance tocetuximab anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively^[how?] months before radiographic progression. It suggests to perform an early initiation of aMEK inhibitor as a rational strategy for delaying or reversing drug resistance.^[25]

KRAS gene can also beamplified in colorectal cancer and tumors harboring this genetic lesion are not responsive toEGFR inhibitors. Although KRAS amplification is infrequent in colorectal cancer, as of 2013 it was hypothesized to be responsible for precluding response to anti-EGFR treatment in some patients.^[26] As of 2015 amplification of wild-type Kras has also been observed inovarian,^[27]gastric,uterine, andlung cancers.^[28]

Whether a patient is positive or negative for a mutation in theepidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such aserlotinib (Tarceva) orgefitinib (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 regulatingcell growth,differentiation andapoptosis. The different expression of these genes inKRAS-mutant tumors might have a more prominent role in affecting patient's clinical outcomes.^[32]

A 2008 paper published inCancer Research concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumorxenografts 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]

Over 90% ofpancreatic ductal adenocarcinomas (PDACs) have a KRAS mutation.^[34][35][36] There is one approved drug,sotorasib, that targets the KRAS G12C mutation, but only ~1% of PDACs have this mutation.^[34] Another KRAS inhibitor,MRTX1133 targets G12D mutation which is present in over 40% of PDACs^[37][38] is currently in clinical trials to treat solid tumors including pancreatic adenocarcinoma.^[39]

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFRmonoclonal antibody drugs indicated for treatment of metastatic colorectal cancer,panitumumab (Vectibix) andcetuximab (Erbitux), to include information aboutKRAS mutations.^[40]

In 2012, the FDA cleared a genetic test byQIAGEN named therascreenKRAS test, designed to detect the presence of seven mutations in theKRAS gene in colorectal cancer cells. This test aids 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.^[41]

Hyperactivating KRAS mutations are known to underlie the pathogenesis of up to 20% of human cancers, making KRAS a desirable target for cancer therapies.^[42] However, development of KRAS-targeting therapies was elusive for decades and KRAS was long referred to as undruggable.^[43] However,Kevan M. Shokat and his colleagues, asHoward Hughes Medical Institute investigators at theUniversity of California, discovered a druggable "Achilles heel" on KRAS (specifically the KRAS-G12C mutant), which enabled the development of the first KRAS-targeting drugs by pharmaceutical companies based on their breakthrough findings.^{[44][45][46][47]}

Currently, a few KRAS-targeting drugs are approved for clinical use and, many clinical trials are underway, exploring the therapeutic potential of a wide variety of KRAS-targeting drugs.

Anantisense oligonucleotide (ASO) targeting KRAS,AZD4785 (AstraZeneca/Ionis Therapeutics), completed a phase I study^[48] but in 2019 was discontinued from further development because of insufficientknockdown of the target.^[49]

As of October 2025, there are clinical trials exploring the therapeutic potential of several pan-KRAS targeting drugs includingdaraxonrasib,KO-2806,AMG410, and the peptide inhibitorLUNA18.

One fairly frequent driver mutation is KRAS^G12C.Electrophilic KRAS inhibitors can form irreversiblecovalent bonds withnucleophilic sulfur atom of Cys-12 and hence selectively target KRAS^G12C and leave wild-type KRAS untouched.^[52]

In 2021, the U.S. FDA approved one KRAS^G12C mutantcovalent inhibitor,sotorasib (AMG 510,Amgen) for the treatment ofnon-small cell lung cancer (NSCLC), the first KRAS inhibitor to reach the market and enter clinical use.^[53][54]

A second isadagrasib (MRTX-849,Mirati Therapeutics)^[55][56] while JNJ-74699157 (also known as ARS-3248,Wellspring Biosciences/Janssen) has received aninvestigational new drug (IND) approval to start clinical trials.^[57]

A phase Ia/Ib dose escalation trial of the oral selectiveKRAS G12C inhibitordivarasib was published in 2023, where the drug was tested in non-small cell lung cancer, colorectal cancer, and other solid tumors withKRAS G12C mutations.^[58] It continues in phase I and II studies for several cancer types as of August 2023.^{[59][60][61][62]}

The most commonKRAS mutation is G12D which is estimated to be present in up to 37% pancreatic cancers and over 12% of colorectal cancers. As of October 2025, there are several G12D targeting drugs in clinical or preclinical trials including Zoldonrasib, INCB161734, LY3962673, AZD0022, and the PROTAC ASP3082.

In 2021, the first clinical trial of a gene therapy targeting KRAS G12D was recruiting patients, sponsored by theNational Cancer Institute.^[63] In June 2022, a case report was published about a 71-year-old woman with metastatic pancreatic cancer after extensive treatment (Whipple Surgery, radiation and multiple agent chemotherapy) who received a single infusion ofengineered T cells directed to both the G12D mutation and an HLA allele. Her tumor regressed persistently. But another similarly treated patient died from the cancer.^[64]

The G12V mutation can be targeted by the drug RMC-5127 which is undergoing clinical trials as of October 2025.

KRAS has been shown tointeract with many molecules including:

• C-Raf^[65][66]
• PIK3CG^[67]
• RALGDS^[65][68]
• RASSF2^[69]
• Calmodulin^[70]

• KRAS Reference Standards - Learn more about KRAS Reference Controls
• GeneReviews/NCBI/NIH/UW entry on Cardiofaciocutaneous Syndrome
• GeneReviews/NCBI/NIH/UW entry on Noonan syndrome
• KRAS2+protein,+human at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• Overview of all the structural information available in thePDB forUniProt:P01116 (Human GTPase KRas) at thePDBe-KB.

• Genes on human chromosome 12
• Oncogenes

• Articles with short description
• Short description is different from Wikidata
• Wikipedia articles needing clarification from December 2015