KRAS

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For the Slovenian region, see Kras.
Kirsten rat sarcoma viral oncogene homolog
PDB 1d8d EBI.jpg
Rendering of 1D8D
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols KRAS ; C-K-RAS; CFC2; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; KI-RAS; KRAS1; KRAS2; NS; NS3; RASK2
External IDs OMIM190070 MGI96680 HomoloGene37990 GeneCards: KRAS Gene
RNA expression pattern
PBB GE KRAS 204009 s at tn.png
PBB GE KRAS 204010 s at tn.png
PBB GE KRAS 214352 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3845 16653
Ensembl ENSG00000133703 ENSMUSG00000030265
UniProt P01116 P32883
RefSeq (mRNA) NM_004985 NM_021284
RefSeq (protein) NP_004976 NP_067259
Location (UCSC) Chr 12:
25.36 – 25.4 Mb
Chr 6:
145.22 – 145.25 Mb
PubMed search [1] [2]

GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene.[1][2]

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 cancers.[3] Like other members of the Ras family, 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 isoprenyl group on its C-terminus.

Function[edit]

KRAS acts as a molecular on/off switch. Once it is turned on, it recruits and activates proteins necessary for the propagation of growth factor and other receptors' signal such as c-Raf and 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 GTPase-activating protein (GAP) class, for example RasGAP. In turn KRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example SOS1, which forces the release of bound nucleotide. 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 largely in their sites of action within the cell.

Clinical significance[edit]

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, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma.

Several germline KRAS mutations have been found to be associated with Noonan syndrome[4] and cardio-facio-cutaneous syndrome.[5]

Somatic KRAS mutations are found at high rates in leukemias, colon cancer,[6] pancreatic cancer[7] and lung cancer.[8]

Colorectal cancer[edit]

The chronological order of mutations is important in the impact of KRAS mutations in regard to colorectal cancer, with a primary KRAS mutation generally leading to a self-limiting hyperplastic or borderline lesion, but if occurring after a previous APC mutation it often progresses to cancer.[9] KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.[10][11]

KRAS mutation is predictive of a very poor response to panitumumab (Vectibix®) and cetuximab (Erbitux®) therapy in colorectal cancer.[12] 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.[13]

Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies[14][15] 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.[15]

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.[16]

KRAS amplification[edit]

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 anti-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.[17] Amplification of wild-type Kras has also been observed in ovarian, gastric, uterine, and lung cancers.[18]

Lung cancer[edit]

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.[19][20][21] 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.[19]

KRAS Testing[edit]

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.[22]

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.[23]

Interactions[edit]

KRAS has been shown to interact with:

References[edit]

  1. ^ McGrath JP, Capon DJ, Smith DH, Chen EY, Seeburg PH, Goeddel DV, Levinson AD (1983). "Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene". Nature 304 (5926): 501–6. doi:10.1038/304501a0. PMID 6308466. 
  2. ^ Popescu NC, Amsbaugh SC, DiPaolo JA, Tronick SR, Aaronson SA, Swan DC (March 1985). "Chromosomal localization of three human ras genes by in situ molecular hybridization". Somat. Cell Mol. Genet. 11 (2): 149–55. doi:10.1007/BF01534703. PMID 3856955. 
  3. ^ Kranenburg O (November 2005). "The KRAS oncogene: past, present, and future". Biochim. Biophys. Acta 1756 (2): 81–2. doi:10.1016/j.bbcan.2005.10.001. PMID 16269215. 
  4. ^ 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 (March 2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405. 
  5. ^ 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 (March 2006). "Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome". Nat. Genet. 38 (3): 294–6. doi:10.1038/ng1749. PMID 16474404. 
  6. ^ Burmer GC, Loeb LA (1989). "Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma". Proc. Natl. Acad. Sci. U.S.A. 86 (7): 2403–7. doi:10.1073/pnas.86.7.2403. PMC 286921. PMID 2648401. 
  7. ^ Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988). "Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes". Cell 53 (4): 549–54. doi:10.1016/0092-8674(88)90571-5. PMID 2453289. 
  8. ^ Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD, Gazdar AF, Wong MP (March 2006). "Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features". Clin. Cancer Res. 12 (5): 1647–53. doi:10.1158/1078-0432.CCR-05-1981. PMID 16533793. 
  9. ^ Vogelstein B, Kinzler KW (August 2004). "Cancer genes and the pathways they control". Nat. Med. 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780. 
  10. ^ 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. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 2012; 61: 847-54.
  11. ^ 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. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol 2013; 26: 825-34.
  12. ^ 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 (April 2006). "KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer". Cancer Res. 66 (8): 3992–5. doi:10.1158/0008-5472.CAN-06-0191. PMID 16618717. 
  13. ^ L. van Epps, PhD, Heather (Winter 2008). "Bittersweet Gene: A gene called KRAS can predict which colorectal cancers will respond to a certain type of treatment—and which will not.". CURE (Cancer Updates, Research and Education). 
  14. ^ 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 (February 2009). "Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer". J. Clin. Oncol. 27 (5): 663–71. doi:10.1200/JCO.2008.20.8397. PMID 19114683. 
  15. ^ a b 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 (April 2009). "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer". N. Engl. J. Med. 360 (14): 1408–17. doi:10.1056/NEJMoa0805019. PMID 19339720. 
  16. ^ 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 (June 2012). "Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer". Nature 486 (7404): 532–6. doi:10.1038/nature11156. PMID 22722830. 
  17. ^ 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 (September 2013). "KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy". Int. J. Cancer 133 (5): 1259–65. doi:10.1002/ijc.28106. PMID 23404247. 
  18. ^ 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; Hosein, Kouros-Mehr (2014). "Identification of Druggable Cancer Driver Genes Amplified across TCGA Datasets.". PLoS ONE 9 (5): e98293. doi:10.1371/journal.pone.0098293. PMC 4038530. PMID 24874471. 
  19. ^ a b Suda K, Tomizawa K, Mitsudomi T (March 2010). "Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation". Cancer Metastasis Rev. 29 (1): 49–60. doi:10.1007/s10555-010-9209-4. PMID 20108024. 
  20. ^ Riely GJ, Marks J, Pao W (April 2009). "KRAS mutations in non-small cell lung cancer". Proc Am Thorac Soc 6 (2): 201–5. doi:10.1513/pats.200809-107LC. PMID 19349489. 
  21. ^ Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE (January 2005). "KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib". PLoS Med. 2 (1): e17. doi:10.1371/journal.pmed.0020017. PMC 545207. PMID 15696205. 
  22. ^ OncoGenetics.Org (July 2009). "FDA updates Vectibix and Erbitux labels with KRAS testing info". OncoGenetics.Org. Retrieved 2009-07-20. [dead link]
  23. ^ FDA: Medical devices: therascreen® KRAS RGQ PCR Kit - P110030, accessed 20 Jone 2014
  24. ^ a b Li W, Han M, Guan KL (April 2000). "The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf". Genes Dev. 14 (8): 895–900. PMC 316541. PMID 10783161. 
  25. ^ Kiyono M, Kato J, Kataoka T, Kaziro Y, Satoh T (September 2000). "Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1". J. Biol. Chem. 275 (38): 29788–93. doi:10.1074/jbc.M001378200. PMID 10882715. 
  26. ^ Rubio I, Wittig U, Meyer C, Heinze R, Kadereit D, Waldmann H, Downward J, Wetzker R (November 1999). "Farnesylation of Ras is important for the interaction with phosphoinositide 3-kinase gamma". Eur. J. Biochem. 266 (1): 70–82. doi:10.1046/j.1432-1327.1999.00815.x. PMID 10542052. 
  27. ^ Spaargaren M, Bischoff JR (December 1994). "Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap". Proc. Natl. Acad. Sci. U.S.A. 91 (26): 12609–13. doi:10.1073/pnas.91.26.12609. PMC 45488. PMID 7809086. 
  28. ^ Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ (July 2003). "RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor". J. Biol. Chem. 278 (30): 28045–51. doi:10.1074/jbc.M300554200. PMID 12732644. 

Further reading[edit]

  • Kahn S, Yamamoto F, Almoguera C, Winter E, Forrester K, Jordano J, Perucho M (1987). "The c-K-ras gene and human cancer (review)". Anticancer Res. 7 (4A): 639–52. PMID 3310850. 
  • Yamamoto F, Nakano H, Neville C, Perucho M (1985). "Structure and mechanisms of activation of c-K-ras oncogenes in human lung cancer". Prog. Med. Virol. 32: 101–14. PMID 3895297. 
  • Porta M, Ayude D, Alguacil J, Jariod M (2003). "Exploring environmental causes of altered ras effects: fragmentation plus integration?". Mol. Carcinog. 36 (2): 45–52. doi:10.1002/mc.10093. PMID 12557259. 
  • Smakman N, Borel Rinkes IH, Voest EE, Kranenburg O (2006). "Control of colorectal metastasis formation by K-Ras.". Biochim. Biophys. Acta 1756 (2): 103–14. doi:10.1016/j.bbcan.2005.07.001. PMID 16098678. 
  • Castagnola P, Giaretti W (2006). "Mutant KRAS, chromosomal instability and prognosis in colorectal cancer.". Biochim. Biophys. Acta 1756 (2): 115–25. doi:10.1016/j.bbcan.2005.06.003. PMID 16112461. 
  • Deramaudt T, Rustgi AK (2006). "Mutant KRAS in the initiation of pancreatic cancer.". Biochim. Biophys. Acta 1756 (2): 97–101. doi:10.1016/j.bbcan.2005.08.003. PMID 16169155. 
  • Pretlow TP, Pretlow TG (2006). "Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer?". Biochim. Biophys. Acta 1756 (2): 83–96. doi:10.1016/j.bbcan.2005.06.002. PMID 16219426. 
  • Su YH, Wang M, Aiamkitsumrit B, Brenner DE, Block TM (2005). "Detection of a K-ras mutation in urine of patients with colorectal cancer". Cancer Biomark 1 (2-3): 177–82. PMID 17192038. 
  • Domagala P, Hybiak J, Sulzyc-Bielicka V, Cybulski C, Rys J, Domagala W (2012). "KRAS mutation testing in colorectal cancer as an example of the pathologist's role in personalized targeted therapy: a practical approach". Pol. J. Pathol. 63 (3): 145–164. doi:10.5114/PJP.2012.31499. PMID 23161231. 

External links[edit]