KRAS

{{Short description|Protein-coding gene in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{other uses|Kras (disambiguation){{!}}Kras}} {{Infobox_gene}}

'''''KRAS''''' ('''Kirsten rat sarcoma virus oncogene homologue''') is a gene that provides instructions for making a protein called '''K-Ras''', a part of the RAS/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 called ''KRAS'' because it was first identified as a viral oncogene in the '''K'''irsten '''RA'''t '''S'''arcoma virus (current viral nomenclature: Kirsten murine sarcoma virus, ''Gammaretrovirus Kimursar'').<ref>{{cite journal | vauthors = Tsuchida N, Ryder T, Ohtsubo E | title = Nucleotide sequence of the oncogene encoding the p21 transforming protein of Kirsten murine sarcoma virus | journal = Science | volume = 217 | issue = 4563 | pages = 937–939 | date = September 1982 | pmid = 6287573 | doi = 10.1126/science.6287573 | bibcode = 1982Sci...217..937T }}</ref><ref>{{cite web |title=Taxonomy browser Taxonomy Browser (Kirsten murine sarcoma virus) |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=11808 |website=www.ncbi.nlm.nih.gov}}</ref> The oncogene identified was derived from a cellular genome, so {{gene|KRAS}}, when found in a cellular genome, is called a proto-oncogene.

The K-Ras protein is a GTPase, a class of enzymes which convert the nucleotide guanosine triphosphate (GTP) into guanosine diphosphate (GDP). In this way the K-Ras protein acts like a switch 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.

The gene product of ''KRAS'', the K-Ras protein, was first found as a p21 GTPase.<ref>{{cite journal |vauthors= Scolnick EM, Papageoege AG, Shih TY | title= Guanine nucleotide-binding activity for src protein of rat-derived murine sarcoma viruses | journal= Proc Natl Acad Sci USA | volume=76 | issue= 5 | pages= 5355–5559| year=1979 | pmid =228288 | pmc=413141| doi= 10.1073/pnas.76.10.5355 | doi-access= free }}</ref><ref name="pmid16269215">{{cite journal | vauthors = Kranenburg O | title = The KRAS oncogene: past, present, and future | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1756 | issue = 2 | pages = 81–82 | date = November 2005 | pmid = 16269215 | doi = 10.1016/j.bbcan.2005.10.001 }}</ref> Like other members of the ras subfamily of GTPases, the K-Ras protein is an early player in many signal transduction pathways. K-Ras is usually tethered to cell membranes because of the farnesylation of 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 structures in their C-terminal region and use different mechanisms to localize to cellular membranes, including the plasma membrane.<ref name="pmid11030147">{{cite journal | vauthors = Welman A, Burger MM, Hagmann J | title = Structure and function of the C-terminal hypervariable region of K-Ras4B in plasma membrane targetting and transformation | journal = Oncogene | volume = 19 | issue = 40 | pages = 4582–4591 | date = September 2000 | pmid = 11030147 | doi = 10.1038/sj.onc.1203818 | s2cid = 20878317 | doi-access = }}</ref>

== Function ==

''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.<ref name="Yun_2009">{{cite journal | vauthors = Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA, Velculescu VE, Lengauer C, Kinzler KW, Vogelstein B, Papadopoulos N | title = Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells | journal = Science | location = New York, N.Y. | volume = 325 | issue = 5947 | pages = 1555–1559 | date = September 2009 | pmid = 19661383 | pmc = 2820374 | doi = 10.1126/science.1174229 | bibcode = 2009Sci...325.1555Y }}</ref> 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.

==Clinical significance when mutated== 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,<ref>{{cite journal | vauthors = Chiosea SI, Sherer CK, Jelic T, Dacic S | title = KRAS mutant allele-specific imbalance in lung adenocarcinoma | journal = Modern Pathology | volume = 24 | issue = 12 | pages = 1571–1577 | date = December 2011 | pmid = 21743433 | doi = 10.1038/modpathol.2011.109 | doi-access = free }}</ref> mucinous adenoma, ductal carcinoma of the pancreas and colorectal cancer.<ref>{{cite journal | vauthors = Hartman DJ, Davison JM, Foxwell TJ, Nikiforova MN, Chiosea SI | title = Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall survival | journal = International Journal of Cancer | volume = 131 | issue = 8 | pages = 1810–1817 | date = October 2012 | pmid = 22290300 | doi = 10.1002/ijc.27461 | s2cid = 27328214 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Krasinskas AM, Moser AJ, Saka B, Adsay NV, Chiosea SI | title = KRAS mutant allele-specific imbalance is associated with worse prognosis in pancreatic cancer and progression to undifferentiated carcinoma of the pancreas | journal = Modern Pathology | volume = 26 | issue = 10 | pages = 1346–1354 | date = October 2013 | pmid = 23599154 | pmc = 4128625 | doi = 10.1038/modpathol.2013.71 }}</ref>

Several germline KRAS mutations have been found to be associated with Noonan syndrome<ref name="pmid16474405">{{cite journal | vauthors = Schubbert S, Zenker M, Rowe SL, Böll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP | title = Germline KRAS mutations cause Noonan syndrome | journal = Nature Genetics | volume = 38 | issue = 3 | pages = 331–336 | date = March 2006 | pmid = 16474405 | doi = 10.1038/ng1748 | s2cid = 8193354 }}</ref> and cardio-facio-cutaneous syndrome.<ref name="pmid16474404">{{cite journal | vauthors = Niihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y | title = Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome | journal = Nature Genetics | volume = 38 | issue = 3 | pages = 294–296 | date = March 2006 | pmid = 16474404 | doi = 10.1038/ng1749 | s2cid = 28915489 }}</ref> Somatic ''KRAS'' mutations are found at high rates in leukemias, colorectal cancer,<ref>{{cite journal | vauthors = Burmer GC, Loeb LA | title = Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 7 | pages = 2403–2407 | date = April 1989 | pmid = 2648401 | pmc = 286921 | doi = 10.1073/pnas.86.7.2403 | doi-access = free | bibcode = 1989PNAS...86.2403B }}</ref> pancreatic cancer<ref>{{cite journal | vauthors = Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M | title = Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes | journal = Cell | volume = 53 | issue = 4 | pages = 549–554 | date = May 1988 | pmid = 2453289 | doi = 10.1016/0092-8674(88)90571-5 | s2cid = 22457575 }}</ref> and lung cancer.<ref name="pmid16533793">{{cite journal | vauthors = Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD, Gazdar AF, Wong MP | title = Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features | journal = Clinical Cancer Research | volume = 12 | issue = 5 | pages = 1647–1653 | date = March 2006 | pmid = 16533793 | doi = 10.1158/1078-0432.CCR-05-1981 | s2cid = 14795296 | doi-access = }}</ref>

===Colorectal cancer=== 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.<ref name="pmid15286780">{{cite journal | vauthors = Vogelstein B, Kinzler KW | title = Cancer genes and the pathways they control | journal = Nature Medicine | volume = 10 | issue = 8 | pages = 789–799 | date = August 2004 | pmid = 15286780 | doi = 10.1038/nm1087 | s2cid = 205383514 }}</ref> KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.<ref>{{cite journal | vauthors = Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, Liao X, Waldron L, Hoshida Y, Huttenhower C, Chan AT, Giovannucci E, Fuchs C, Ogino S | title = Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum | journal = Gut | volume = 61 | issue = 6 | pages = 847–854 | date = June 2012 | pmid = 22427238 | pmc = 3345105 | doi = 10.1136/gutjnl-2011-300865 }}</ref><ref>{{cite journal | vauthors = Rosty C, Young JP, Walsh MD, Clendenning M, Walters RJ, Pearson S, Pavluk E, Nagler B, Pakenas D, Jass JR, Jenkins MA, Win AK, Southey MC, Parry S, Hopper JL, Giles GG, Williamson E, English DR, Buchanan DD | title = Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features | journal = Modern Pathology | volume = 26 | issue = 6 | pages = 825–834 | date = June 2013 | pmid = 23348904 | doi = 10.1038/modpathol.2012.240 | doi-access = free }}</ref>

As of 2006, KRAS mutation was predictive of a very poor response to panitumumab (Vectibix) and cetuximab (Erbitux) therapy in colorectal cancer.<ref name="pmid16618717">{{cite journal | vauthors = Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P | title = KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer | journal = Cancer Research | volume = 66 | issue = 8 | pages = 3992–3995 | date = April 2006 | pmid = 16618717 | doi = 10.1158/0008-5472.CAN-06-0191 | doi-access = }}</ref>

As of 2008, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-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 the ''KRAS'' gene will not respond to cetuximab or panitumumab.<ref>{{cite news | vauthors = van Epps HL |title= Bittersweet Gene |date=Winter 2008 |publisher=CURE (Cancer Updates, Research and Education) |url=http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/943 |archive-url=https://web.archive.org/web/20090207192642/http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/943 |archive-date=2009-02-07}}</ref>

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<ref name="pmid19114683">{{cite journal | vauthors = Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P | title = Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer | journal = Journal of Clinical Oncology | volume = 27 | issue = 5 | pages = 663–671 | date = February 2009 | pmid = 19114683 | doi = 10.1200/JCO.2008.20.8397 | hdl-access = free | hdl = 2434/652169 }}</ref><ref name="pmid19339720"/> 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-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.<ref name="pmid19339720">{{cite journal | vauthors = Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P | title = Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer | journal = The New England Journal of Medicine | volume = 360 | issue = 14 | pages = 1408–1417 | date = April 2009 | pmid = 19339720 | doi = 10.1056/NEJMoa0805019 | doi-access = free }}</ref>

As of 2012, it was known that emergence of KRAS mutations was 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{{how|date=December 2015}} 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.<ref name="pmid22722830">{{cite journal | vauthors = Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D, Bardelli A | title = Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer | journal = Nature | volume = 486 | issue = 7404 | pages = 532–536 | date = June 2012 | pmid = 22722830 | pmc = 3927413 | doi = 10.1038/nature11156 | bibcode = 2012Natur.486..532M }}</ref>

==== ''KRAS'' amplification ====

''KRAS'' gene can also be amplified in colorectal cancer and tumors harboring this genetic lesion are not responsive to EGFR 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.<ref name="pmid23404247">{{cite journal | vauthors = Valtorta E, Misale S, Sartore-Bianchi A, Nagtegaal ID, Paraf F, Lauricella C, Dimartino V, Hobor S, Jacobs B, Ercolani C, Lamba S, Scala E, Veronese S, Laurent-Puig P, Siena S, Tejpar S, Mottolese M, Punt CJ, Gambacorta M, Bardelli A, Di Nicolantonio F | title = KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy | journal = International Journal of Cancer | volume = 133 | issue = 5 | pages = 1259–1265 | date = September 2013 | pmid = 23404247 | doi = 10.1002/ijc.28106 | hdl-access = free | s2cid = 1791682 | author20-link = Alberto Bardelli | hdl = 2318/132493 }}</ref> As of 2015 amplification of wild-type Kras has also been observed in ovarian,<ref>{{cite journal | vauthors = Sankaranarayanan P, Schomay TE, Aiello KA, Alter O | title = Tensor GSVD of patient- and platform-matched tumor and normal DNA copy-number profiles uncovers chromosome arm-wide patterns of tumor-exclusive platform-consistent alterations encoding for cell transformation and predicting ovarian cancer survival | journal = PLOS ONE | volume = 10 | issue = 4 | article-number = e0121396 | date = April 2015 | pmid = 25875127 | pmc = 4398562 | doi = 10.1371/journal.pone.0121396 | id = [http://www.eurekalert.org/pub_releases/2015-04/uouh-nmi040915.php AAAS EurekAlert! Press Release] and [https://www.nae.edu/Projects/20730/wtop/134897.aspx NAE Podcast Feature] | bibcode = 2015PLoSO..1021396S | doi-access = free }}</ref> gastric, uterine, and lung cancers.<ref>{{cite journal | vauthors = Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y, Hamm N, Ma X, Higgs RE, Bhagwat SV, Buchanan S, Peng SB, Staschke KA, Yadav V, Yue Y, Kouros-Mehr H | title = Identification of druggable cancer driver genes amplified across TCGA datasets | journal = PLOS ONE | volume = 9 | issue = 5 | article-number = e98293 | date = 2014 | pmid = 24874471 | pmc = 4038530 | doi = 10.1371/journal.pone.0098293 | doi-access = free | bibcode = 2014PLoSO...998293C }}</ref>

=== Lung cancer ===

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.<ref name="pmid20108024">{{cite journal | vauthors = Suda K, Tomizawa K, Mitsudomi T | title = Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation | journal = Cancer and Metastasis Reviews | volume = 29 | issue = 1 | pages = 49–60 | date = March 2010 | pmid = 20108024 | doi = 10.1007/s10555-010-9209-4 | s2cid = 19626219 }}</ref><ref name="pmid19349489">{{cite journal | vauthors = Riely GJ, Marks J, Pao W | title = KRAS mutations in non-small cell lung cancer | journal = Proceedings of the American Thoracic Society | volume = 6 | issue = 2 | pages = 201–205 | date = April 2009 | pmid = 19349489 | doi = 10.1513/pats.200809-107LC }}</ref><ref name="pmid15696205">{{cite journal | vauthors = Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE | title = KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib | journal = PLOS Medicine | volume = 2 | issue = 1 | article-number = e17 | date = January 2005 | pmid = 15696205 | pmc = 545207 | doi = 10.1371/journal.pmed.0020017 | doi-access = free }}</ref> 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.<ref name="pmid20108024"/>

Different types of data including mutation status and gene expression did not have a significant prognostic power.<ref name="Nagy_2017">{{cite journal | vauthors = Nagy Á, Pongor LS, Szabó A, Santarpia M, Győrffy B | title = KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer | journal = International Journal of Cancer | volume = 140 | issue = 4 | pages = 930–937 | date = February 2017 | pmid = 27859136 | pmc = 5299512 | doi = 10.1002/ijc.30509 }}</ref> No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC).<ref name="Nagy_2017" /> 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.<ref name="Nagy_2017" />

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."<ref name="pmid18794128">{{cite journal | vauthors = Guo W, Wu S, Liu J, Fang B | title = Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota | journal = Cancer Research | volume = 68 | issue = 18 | pages = 7403–7408 | date = September 2008 | pmid = 18794128 | pmc = 2678915 | doi = 10.1158/0008-5472.CAN-08-1449 }}</ref>

=== Pancreatic cancer===

Over 90% of pancreatic ductal adenocarcinomas (PDACs) have a KRAS mutation.<ref name="Leroux_2021">{{cite journal | vauthors = Leroux C, Konstantinidou G | title = Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology | journal = Cancers | volume = 13 | issue = 4 | date = February 2021 | page = 799 | pmid = 33672917 | pmc = 7918504 | doi = 10.3390/cancers13040799 | doi-access = free }}</ref><ref name = "Lee_2023">{{cite book | vauthors = Lee MS, Pant S | chapter = Targeted Therapies for Pancreatic Cancer | veditors = Pant S |title = Pancreatic Cancer | publisher = Springer | location = Cham |date= November 2023 |pages=67–95 |doi=10.1007/978-3-031-38623-7_5 | isbn = 978-3-031-38623-7 }}</ref><ref name = "Rosenzwieg_2021">{{cite web | title = 5 Things to Know About Targeting Mutant KRAS in Pancreatic Cancer | url = https://pancan.org/news/5-things-to-know-about-targeting-mutant-kras-in-pancreatic-cancer/ | vauthors = Rosenzwieg A | date = 8 June 2021 | work = Pancreatic Cancer Action Network }}</ref> There is one approved drug, sotorasib, that targets the KRAS G12C mutation, but only ~1% of PDACs have this mutation.<ref name="Leroux_2021" /> Another KRAS inhibitor, MRTX1133 targets G12D mutation which is present in over 40% of PDACs<ref name="pmid37831007">{{cite journal | vauthors = Wei D, Wang L, Zuo X, Maitra A, Bresalier RS | title = A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer | journal = Clinical Cancer Research | volume = 30 | issue = 4 | pages = 655–662 | date = February 2024 | pmid = 37831007 | doi = 10.1158/1078-0432.CCR-23-2098 | pmc = 10922474 | s2cid = 263967602 }}</ref><ref name="Bannoura_2022">{{cite journal | vauthors = Bannoura SF, Khan HY, Azmi AS | title = KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered? | journal = Frontiers in Oncology | volume = 12 | issue = | article-number = 1013902 | date = 2022 | pmid = 36531078 | pmc = 9749787 | doi = 10.3389/fonc.2022.1013902 | doi-access = free }}</ref> is currently in clinical trials to treat solid tumors including pancreatic adenocarcinoma.<ref>{{ClinicalTrialsGov|NCT05737706|Study of MRTX1133 in Patients With Advanced Solid Tumors Harboring a KRAS G12D Mutation}}</ref>

==''KRAS'' testing== 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.<ref>{{cite web|url=http://www.oncogenetics.org/web/fda-updates-vectibix-and-erbitux-labels-with-kras-testing-info |title=FDA updates Vectibix and Erbitux labels with KRAS testing info |author=OncoGenetics.Org |publisher=OncoGenetics.Org |access-date=2009-07-20 |date=July 2009 |archive-url=https://web.archive.org/web/20141109174052/http://www.oncogenetics.org/web/fda-updates-vectibix-and-erbitux-labels-with-kras-testing-info |archive-date=November 9, 2014 }}</ref>

In 2012, the FDA cleared a genetic test by QIAGEN named therascreen ''KRAS'' test, designed to detect the presence of seven mutations in the ''KRAS'' 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.<ref>[https://web.archive.org/web/20121019090830/http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm312055.htm FDA: Medical devices: therascreen® KRAS RGQ PCR Kit – P110030, accessed 20 Jone 2014]</ref>

== As a therapeutic target ==

{{cs1 config|name-list-style=vanc|display-authors=6}} Hyperactivating KRAS mutations are known to underlie the pathogenesis of up to 20% of human cancers, making KRAS a desirable target for cancer therapies.<ref name="Cox_2014">{{cite journal | vauthors = Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ | title = Drugging the undruggable RAS: Mission possible? | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 11 | pages = 828–851 | date = November 2014 | pmid = 25323927 | pmc = 4355017 | doi = 10.1038/nrd4389 }}</ref> However, development of KRAS-targeting therapies was elusive for decades and KRAS was long referred to as undruggable.<ref>{{Cite web | title = Researchers identify new mechanism to target 'undruggable' cancer gene | url = https://www.sciencedaily.com/releases/2016/04/160421133651.htm | access-date = 2017-01-17 | publisher = www.sciencedaily.com }}</ref> However, Kevan M. Shokat and his colleagues, as Howard Hughes Medical Institute investigators at the University 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.<ref>{{cite journal | vauthors = Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM | title = K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions | journal = Nature | volume = 503 | issue = 7477 | pages = 548–551 | date = November 2013 | pmid = 24256730 | doi = 10.1038/nature12796 | pmc = 4274051 | bibcode = 2013Natur.503..548O }}</ref><ref>{{cite journal | vauthors = Ostrem JM, Shokat KM | title = Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design | journal = Nature Reviews. Drug Discovery | volume = 15 | issue = 11 | pages = 771–785 | date = November 2016 | pmid = 27469033 | doi = 10.1038/nrd.2016.139 }}</ref><ref>{{cite journal | vauthors = Orgován Z, Keserű GM | title = Small molecule inhibitors of RAS proteins with oncogenic mutations | journal = Cancer and Metastasis Reviews | volume = 39 | issue = 4 | pages = 1107–1126 | date = December 2020 | pmid = 32770300 | doi = 10.1007/s10555-020-09911-9 | pmc = 7680341 }}</ref><ref>{{cite journal | vauthors = Sabt A, Tawfik HO, Khaleel EF, Badi RM, Ibrahim HA, Elkaeed EB, Eldehna WM | title = An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review | journal = Molecular Diversity | volume = 28 | issue = 6 | pages = 4581–4608 | date = December 2024 | pmid = 38289431 | doi = 10.1007/s11030-023-10777-6 }}</ref>

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.

=== Pan-KRAS (WT or any mutation) === An antisense oligonucleotide (ASO) targeting KRAS, AZD4785 (AstraZeneca/Ionis Therapeutics), completed a phase I study<ref>{{ClinicalTrialsGov|NCT03101839|Phase I Dose-Escalation Study of AZD4785 in Patients With Advanced Solid Tumours}}</ref> but in 2019 was discontinued from further development because of insufficient knockdown of the target.<ref>{{cite web | vauthors = Plieth J | title = Astra's first attempt fails, but there's no giving up on KRAS | url = https://www.evaluate.com/vantage/articles/news/trial-results/astras-first-attempt-fails-theres-no-giving-kras | work = Evaluate | date = 26 April 2019 }}</ref> Development of a peptide inhibitor paluratide (LUNA18) was discontinued in July 2025 due to a narrow therapeutic window.<ref name="Fierce2025">{{cite web | vauthors = Taylor NP | title = Roche axes 4 Chugai solid tumor assets in early-phase clear-out | date = 24 October 2025 | url = https://www.fiercebiotech.com/biotech/roche-axes-4-chugai-solid-tumor-assets-early-phase-clearout | work = Fierce Biotech }}</ref>

As of October 2025, there are clinical trials exploring the therapeutic potential of several pan-KRAS targeting drugs including daraxonrasib, darlifarnib (KO-2806, a farnesyl transferase inhibitor),<ref>{{cite web|title=darlifarnib|work=NCI's Drug Dictionary|publisher=National Cancer Institute (NCI)|url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/darlifarnib|access-date=31 May 2026}}</ref> AMG410.

=== G12C mutation === [[File:KRAS protein G12C mutant with GDP and sotorasib 6OIM.png|thumb|Surface model of a KRAS^G12C protein, showing a GDP molecule (orange) in its high-affinity binding site and the covalent inhibitor sotorasib (aqua) occupying an adjacent "cryptic" binding pocket. Sotorasib forms an irreversible bond with a cysteine residue and disrupts function of the mutated protein. From {{PDB|6OIM}}.<ref name="Canon_2019">{{cite journal | vauthors = Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR | title = The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity | journal = Nature | volume = 575 | issue = 7781 | pages = 217–223 | date = November 2019 | pmid = 31666701 | doi = 10.1038/s41586-019-1694-1 | s2cid = 204969251 | bibcode = 2019Natur.575..217C }}</ref><ref name="Lanman_2020">{{cite journal | vauthors = Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang HL, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, San Miguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, Cee VJ | title = Discovery of a Covalent Inhibitor of KRAS^G12C (AMG 510) for the Treatment of Solid Tumors | journal = Journal of Medicinal Chemistry | volume = 63 | issue = 1 | pages = 52–65 | date = January 2020 | pmid = 31820981 | doi = 10.1021/acs.jmedchem.9b01180 | s2cid = 209313106 | doi-access = free }}</ref>]]

One fairly frequent driver mutation is KRAS^G12C. Electrophilic KRAS inhibitors can form irreversible covalent bonds with nucleophilic sulfur atom of Cys-12 and hence selectively target KRAS^G12C and leave wild-type KRAS untouched.<ref name="pmid30705085">{{cite journal | vauthors = McCormick F | title = Progress in targeting RAS with small molecule drugs | journal = The Biochemical Journal | volume = 476 | issue = 2 | pages = 365–374 | date = January 2019 | pmid = 30705085 | doi = 10.1042/BCJ20170441 | s2cid = 73414179 | doi-access = free }}</ref>

In 2021, the U.S. FDA approved one KRAS^G12C mutant covalent inhibitor, sotorasib (AMG 510, Amgen) for the treatment of non-small cell lung cancer (NSCLC), the first KRAS inhibitor to reach the market and enter clinical use.<ref name="FDA PR 20210528">{{cite web | title=FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy | website=U.S. Food and Drug Administration (FDA) | date=28 May 2021 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug | archive-url=https://web.archive.org/web/20210528171655/http://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug | archive-date=May 28, 2021 | access-date=28 May 2021}}</ref><ref>{{cite web |url=https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-sotorasib-lung-cancer-kras |author=NCI Staff |title=Sotorasib is First KRAS Inhibitor Approved by FDA - NCI |date=2021-06-25 |work=Cancer Currents |publisher=National Cancer Institute |access-date=2022-06-04}}</ref>

A second is adagrasib (MRTX-849, Mirati Therapeutics)<ref>{{ClinicalTrialsGov|NCT03785249|MRTX849 in Patients With Cancer Having a KRAS G12C Mutation}}</ref><ref>{{Cite web |url= https://www.science.org/content/article/two-new-drugs-finally-hit-undruggable-cancer-target-providing-hope-treatments |title=Two new drugs finally hit 'undruggable' cancer target, providing hope for treatments| vauthors = Kaiser J |date=2019-10-30 | work = Science Magazine | publisher = AAAS |access-date=2019-11-04 }}</ref> while JNJ-74699157 (also known as ARS-3248, Wellspring Biosciences/Janssen) has received an investigational new drug (IND) approval to start clinical trials.<ref name="Mullard_2019">{{cite journal | vauthors = Mullard A | title = KRAS's undruggability cracks? | journal = Nature Reviews. Drug Discovery | volume = 18 | issue = 7 | page = 488 | date = July 2019 | pmid = 31267080 | doi = 10.1038/d41573-019-00102-y | doi-access = free }}</ref>

A phase Ia/Ib dose escalation trial of the oral selective ''KRAS'' G12C inhibitor divarasib was published in 2023, where the drug was tested in non-small cell lung cancer, colorectal cancer, and other solid tumors with ''KRAS'' G12C mutations.<ref>{{cite journal | vauthors = Sacher A, LoRusso P, Patel MR, Miller WH, Garralda E, Forster MD, Santoro A, Falcon A, Kim TW, Paz-Ares L, Bowyer S, de Miguel M, Han SW, Krebs MG, Lee JS, Cheng ML, Arbour K, Massarelli E, Choi Y, Shi Z, Mandlekar S, Lin MT, Royer-Joo S, Chang J, Dharia NV, Schutzman JL, Desai J | title = Single-Agent Divarasib (GDC-6036) in Solid Tumors with a ''KRAS'' G12C Mutation | journal = The New England Journal of Medicine | volume = 389 | issue = 8 | pages = 710–721 | date = August 2023 | pmid = 37611121 | doi = 10.1056/NEJMoa2303810 | hdl = 2268/311523 | s2cid = 261098837 | hdl-access = free }}</ref> It continues in phase I and II studies for several cancer types as of August 2023.<ref>{{Cite web |title=Study Record {{!}} A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer |url=https://clinicaltrials.gov/study/NCT04302025 |access-date=2023-08-26 |website=clinicaltrials.gov}}</ref><ref>{{Cite web |title=Study Record {{!}} A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) |url=https://clinicaltrials.gov/study/NCT04929223 |access-date=2023-08-26 |website=clinicaltrials.gov}}</ref><ref>{{Cite web |title=Study Record {{!}} A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation |url=https://clinicaltrials.gov/study/NCT04449874 |access-date=2023-08-26 |website=clinicaltrials.gov}}</ref><ref>{{Cite web |title=Study Record {{!}} A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC) (B-FAST) |url=https://clinicaltrials.gov/study/NCT03178552 |access-date=2023-08-26 |website=clinicaltrials.gov}}</ref>

In China, garsorasib is approved for the treatment of advanced non-small cell lung cancer (NSCLC) carrying the KRAS G12C mutation in patients who have received at least one systemic treatment.<ref>{{cite web | url = https://english.nmpa.gov.cn/2025-02/19/c_1073662.htm | title = Garsorasib Tablets Approved with Conditions for Marketing by China NMPA | date = 2025-02-19 | publisher = National Medical Products Administration }}</ref>

===G12D mutation=== The most common ''KRAS'' 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 the National Cancer Institute.<ref>{{cite web |title=A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients |url=https://clinicaltrials.gov/ct2/show/NCT03745326 |publisher=clinicaltrials.gov |access-date=26 July 2021 |date=28 January 2021}}</ref> 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 of engineered 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.<ref name="nejm">{{cite journal | vauthors = Leidner R, Sanjuan Silva N, Huang H, Sprott D, Zheng C, Shih YP, Leung A, Payne R, Sutcliffe K, Cramer J, Rosenberg SA, Fox BA, Urba WJ, Tran E | title = Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer | journal = The New England Journal of Medicine | volume = 386 | issue = 22 | pages = 2112–2119 | date = June 2022 | pmid = 35648703 | pmc = 9531755 | doi = 10.1056/NEJMoa2119662 }}</ref>

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

== Interactions ==

KRAS has been shown to interact with many molecules including: * C-Raf<ref name="pmid10783161">{{cite journal | vauthors = Li W, Han M, Guan KL | title = The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf | journal = Genes & Development | volume = 14 | issue = 8 | pages = 895–900 | date = April 2000 | pmid = 10783161 | pmc = 316541 | doi = 10.1101/gad.14.8.895 }}</ref><ref name="pmid10882715">{{cite journal | vauthors = Kiyono M, Kato J, Kataoka T, Kaziro Y, Satoh T | title = Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29788–29793 | date = September 2000 | pmid = 10882715 | doi = 10.1074/jbc.M001378200 | doi-access = free }}</ref> * PIK3CG<ref name="pmid10542052">{{cite journal | vauthors = Rubio I, Wittig U, Meyer C, Heinze R, Kadereit D, Waldmann H, Downward J, Wetzker R | title = Farnesylation of Ras is important for the interaction with phosphoinositide 3-kinase gamma | journal = European Journal of Biochemistry | volume = 266 | issue = 1 | pages = 70–82 | date = November 1999 | pmid = 10542052 | doi = 10.1046/j.1432-1327.1999.00815.x | doi-access = free }}</ref> * RALGDS<ref name=pmid10783161/><ref name="pmid7809086">{{cite journal | vauthors = Spaargaren M, Bischoff JR | title = Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 26 | pages = 12609–12613 | date = December 1994 | pmid = 7809086 | pmc = 45488 | doi = 10.1073/pnas.91.26.12609 | doi-access = free | bibcode = 1994PNAS...9112609S }}</ref> * RASSF2<ref name="pmid12732644">{{cite journal | vauthors = Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ | title = RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 30 | pages = 28045–28051 | date = July 2003 | pmid = 12732644 | doi = 10.1074/jbc.M300554200 | doi-access = free }}</ref> * Calmodulin<ref>{{cite journal | vauthors = Villalonga P, López-Alcalá C, Bosch M, Chiloeches A, Rocamora N, Gil J, Marais R, Marshall CJ, Bachs O, Agell N | title = Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling | journal = Molecular and Cellular Biology | volume = 21 | issue = 21 | pages = 7345–7354 | date = November 2001 | pmid = 11585916 | pmc = 99908 | doi = 10.1128/MCB.21.21.7345-7354.2001 }}</ref>

== References == {{Reflist}}

== Further reading == {{Refbegin|30em}} * {{cite journal | vauthors = Kahn S, Yamamoto F, Almoguera C, Winter E, Forrester K, Jordano J, Perucho M | title = The c-K-ras gene and human cancer (review) | journal = Anticancer Research | volume = 7 | issue = 4A | pages = 639–652 | year = 1987 | pmid = 3310850 }} * {{cite journal | vauthors = Yamamoto F, Nakano H, Neville C, Perucho M | title = Structure and mechanisms of activation of c-K-ras oncogenes in human lung cancer | journal = Progress in Medical Virology | volume = 32 | pages = 101–114 | year = 1985 | pmid = 3895297 }} * {{cite journal | vauthors = Porta M, Ayude D, Alguacil J, Jariod M | title = Exploring environmental causes of altered ras effects: fragmentation plus integration? | journal = Molecular Carcinogenesis | volume = 36 | issue = 2 | pages = 45–52 | date = February 2003 | pmid = 12557259 | doi = 10.1002/mc.10093 | s2cid = 23937262 }} * {{cite journal | vauthors = Smakman N, Borel Rinkes IH, Voest EE, Kranenburg O | title = Control of colorectal metastasis formation by K-Ras | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1756 | issue = 2 | pages = 103–114 | date = November 2005 | pmid = 16098678 | doi = 10.1016/j.bbcan.2005.07.001 }} * {{cite journal | vauthors = Castagnola P, Giaretti W | title = Mutant KRAS, chromosomal instability and prognosis in colorectal cancer | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1756 | issue = 2 | pages = 115–125 | date = November 2005 | pmid = 16112461 | doi = 10.1016/j.bbcan.2005.06.003 }} * {{cite journal | vauthors = Deramaudt T, Rustgi AK | title = Mutant KRAS in the initiation of pancreatic cancer | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1756 | issue = 2 | pages = 97–101 | date = November 2005 | pmid = 16169155 | doi = 10.1016/j.bbcan.2005.08.003 }} * {{cite journal | vauthors = Pretlow TP, Pretlow TG | title = Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer? | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1756 | issue = 2 | pages = 83–96 | date = November 2005 | pmid = 16219426 | doi = 10.1016/j.bbcan.2005.06.002 }} * {{cite journal | vauthors = Su YH, Wang M, Aiamkitsumrit B, Brenner DE, Block TM | title = Detection of a K-ras mutation in urine of patients with colorectal cancer | journal = Cancer Biomarkers | volume = 1 | issue = 2–3 | pages = 177–182 | year = 2005 | pmid = 17192038 | doi = 10.3233/CBM-2005-12-305 }} * {{cite journal | vauthors = Domagała P, Hybiak J, Sulżyc-Bielicka V, Cybulski C, Ryś J, Domagała W | title = KRAS mutation testing in colorectal cancer as an example of the pathologist's role in personalized targeted therapy: a practical approach | journal = Polish Journal of Pathology | volume = 63 | issue = 3 | pages = 145–164 | date = November 2012 | pmid = 23161231 | doi = 10.5114/PJP.2012.31499 | arxiv = 1305.1286 | s2cid = 17666526 }} {{Refend}}

== External links == * [https://www.horizondiscovery.com/kras-gene-specific-multiplex-reference-standard-hd748 KRAS Reference Standards] - Learn more about KRAS Reference Controls * [https://www.ncbi.nlm.nih.gov/books/NBK1186/ GeneReviews/NCBI/NIH/UW entry on Cardiofaciocutaneous Syndrome] * [https://www.ncbi.nlm.nih.gov/books/NBK1124/ GeneReviews/NCBI/NIH/UW entry on Noonan syndrome] * {{MeshName|KRAS2+protein,+human}} * {{PDBe-KB2|P01116|Human GTPase KRas}}

{{PDB Gallery|geneid=3845}} {{Acid anhydride hydrolases}}

Category:Oncogenes