KRAS

For the Slovenian region, see Kras.
Kirsten rat sarcoma viral oncogene homolog

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 OMIM: 190070 MGI: 96680 HomoloGene: 37990 GeneCards: KRAS Gene
RNA expression pattern
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:
25.2 – 25.25 Mb		 Chr 6:
145.22 – 145.25 Mb
PubMed search

KRAS (pronounced "k-ras") also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, is a GTPase 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 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 utilise different mechanisms to localize to cellular membranes including plasma membrane.[4]

Function

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 upregulates the GLUT1 glucose transporter, thereby contributing to the Warburg effect in cancer cells.[5] 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 (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

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,[6] mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma.[7][8]

Several germline KRAS mutations have been found to be associated with Noonan syndrome[9] and cardio-facio-cutaneous syndrome.[10]

Somatic KRAS mutations are found at high rates in leukemias, colon cancer,[11] pancreatic cancer[12] and lung cancer.[13]

Colorectal cancer

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.[14] KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.[15][16]

KRAS mutation is predictive of a very poor response to panitumumab (Vectibix®) and cetuximab (Erbitux®) therapy in colorectal cancer.[17] 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.[18]

Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies[19][20] 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.[20]

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.[21]

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 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.[22] Amplification of wild-type Kras has also been observed in ovarian,[23] gastric, uterine, and lung cancers.[24]

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.[25][26][27] 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.[25]

KRAS Testing

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.[28]

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.[29]

Interactions

KRAS has been shown to interact with:

References

  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 (Mar 1985). "Chromosomal localization of three human ras genes by in situ molecular hybridization". Somatic Cell and Molecular Genetics 11 (2): 149–55. doi:10.1007/BF01534703. PMID 3856955.
  3. ↑ Kranenburg O (Nov 2005). "The KRAS oncogene: past, present, and future". Biochimica et Biophysica Acta 1756 (2): 81–2. doi:10.1016/j.bbcan.2005.10.001. PMID 16269215.
  4. ↑ Welman A, Burger MM, Hagmann J (Sep 2000). "Structure and function of the C-terminal hypervariable region of K-Ras4B in plasma membrane targetting and transformation". Oncogene 19 (40): 4582–91. doi:10.1038/sj.onc.1203818. PMID 11030147.
  5. ↑ 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 (Sep 2009). "Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells". Science 325 (5947): 1555–9. doi:10.1126/science.1174229. PMC 2820374. PMID 19661383.
  6. ↑ Chiosea SI, Sherer CK, Jelic T, Dacic S (Dec 2011). "KRAS mutant allele-specific imbalance in lung adenocarcinoma". Modern Pathology 24 (12): 1571–7. doi:10.1038/modpathol.2011.109. PMID 21743433.
  7. ↑ Hartman DJ, Davison JM, Foxwell TJ, Nikiforova MN, Chiosea SI (Oct 2012). "Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall survival". International Journal of Cancer. Journal International Du Cancer 131 (8): 1810–7. doi:10.1002/ijc.27461. PMID 22290300.
  8. ↑ Krasinskas AM, Moser AJ, Saka B, Adsay NV, Chiosea SI (Oct 2013). "KRAS mutant allele-specific imbalance is associated with worse prognosis in pancreatic cancer and progression to undifferentiated carcinoma of the pancreas". Modern Pathology 26 (10): 1346–54. doi:10.1038/modpathol.2013.71. PMC 4128625. PMID 23599154.
  9. ↑ 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 (Mar 2006). "Germline KRAS mutations cause Noonan syndrome". Nature Genetics 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405.
  10. ↑ 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 (Mar 2006). "Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome". Nature Genetics 38 (3): 294–6. doi:10.1038/ng1749. PMID 16474404.
  11. ↑ Burmer GC, Loeb LA (Apr 1989). "Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma". Proceedings of the National Academy of Sciences of the United States of America 86 (7): 2403–7. doi:10.1073/pnas.86.7.2403. PMC 286921. PMID 2648401.
  12. ↑ Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (May 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.
  13. ↑ Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD, Gazdar AF, Wong MP (Mar 2006). "Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features". Clinical Cancer Research 12 (5): 1647–53. doi:10.1158/1078-0432.CCR-05-1981. PMID 16533793.
  14. ↑ Vogelstein B, Kinzler KW (Aug 2004). "Cancer genes and the pathways they control". Nature Medicine 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780.
  15. ↑ 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 (Jun 2012). "Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum". Gut 61 (6): 847–54. doi:10.1136/gutjnl-2011-300865. PMC 3345105. PMID 22427238.
  16. ↑ 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 (Jun 2013). "Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features". Modern Pathology 26 (6): 825–34. doi:10.1038/modpathol.2012.240. PMID 23348904.
  17. ↑ 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 (Apr 2006). "KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer". Cancer Research 66 (8): 3992–5. doi:10.1158/0008-5472.CAN-06-0191. PMID 16618717.
  18. ↑ 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).
  19. ↑ 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 (Feb 2009). "Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer". Journal of Clinical Oncology 27 (5): 663–71. doi:10.1200/JCO.2008.20.8397. PMID 19114683.
  20. 1 2 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 (Apr 2009). "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer". The New England Journal of Medicine 360 (14): 1408–17. doi:10.1056/NEJMoa0805019. PMID 19339720.
  21. ↑ 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 (Jun 2012). "Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer". Nature 486 (7404): 532–6. doi:10.1038/nature11156. PMC 3927413. PMID 22722830.
  22. ↑ 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 (Sep 2013). "KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy". International Journal of Cancer. Journal International Du Cancer 133 (5): 1259–65. doi:10.1002/ijc.28106. PMID 23404247.
  23. ↑ Sankaranarayanan P, Schomay TE, Aiello KA, Alter O (April 2015). "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". PLOS ONE 10 (4): e0121396. doi:10.1371/journal.pone.0121396. PMID 25875127. AAAS EurekAlert! Press Release and NAE Podcast Feature.
  24. ↑ 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 (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.
  25. 1 2 Suda K, Tomizawa K, Mitsudomi T (Mar 2010). "Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation". Cancer Metastasis Reviews 29 (1): 49–60. doi:10.1007/s10555-010-9209-4. PMID 20108024.
  26. ↑ Riely GJ, Marks J, Pao W (Apr 2009). "KRAS mutations in non-small cell lung cancer". Proceedings of the American Thoracic Society 6 (2): 201–5. doi:10.1513/pats.200809-107LC. PMID 19349489.
  27. ↑ Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE (Jan 2005). "KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib". PLoS Medicine 2 (1): e17. doi:10.1371/journal.pmed.0020017. PMC 545207. PMID 15696205.
  28. ↑ OncoGenetics.Org (July 2009). "FDA updates Vectibix and Erbitux labels with KRAS testing info". OncoGenetics.Org. Archived from the original on November 9, 2014. Retrieved 2009-07-20.
  29. ↑ FDA: Medical devices: therascreen® KRAS RGQ PCR Kit - P110030, accessed 20 Jone 2014
  30. 1 2 Li W, Han M, Guan KL (Apr 2000). "The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf". Genes & Development 14 (8): 895–900. PMC 316541. PMID 10783161.
  31. ↑ Kiyono M, Kato J, Kataoka T, Kaziro Y, Satoh T (Sep 2000). "Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1". The Journal of Biological Chemistry 275 (38): 29788–93. doi:10.1074/jbc.M001378200. PMID 10882715.
  32. ↑ Rubio I, Wittig U, Meyer C, Heinze R, Kadereit D, Waldmann H, Downward J, Wetzker R (Nov 1999). "Farnesylation of Ras is important for the interaction with phosphoinositide 3-kinase gamma". European Journal of Biochemistry / FEBS 266 (1): 70–82. doi:10.1046/j.1432-1327.1999.00815.x. PMID 10542052.
  33. ↑ Spaargaren M, Bischoff JR (Dec 1994). "Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap". Proceedings of the National Academy of Sciences of the United States of America 91 (26): 12609–13. doi:10.1073/pnas.91.26.12609. PMC 45488. PMID 7809086.
  34. ↑ Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ (Jul 2003). "RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor". The Journal of Biological Chemistry 278 (30): 28045–51. doi:10.1074/jbc.M300554200. PMID 12732644.
  35. ↑ Villalonga, P.; López-Alcalá, C.; Bosch, M.; Chiloeches, A.; Rocamora, N.; Gil, J.; Marais, R.; Marshall, C. J.; Bachs, O. (2001-11-01). "Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling". Molecular and Cellular Biology 21 (21): 7345–7354. doi:10.1128/MCB.21.21.7345-7354.2001. ISSN 0270-7306. PMC 99908. PMID 11585916.

Further reading

  • 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 Research 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". Progress in Medical Virology. Fortschritte Der Medizinischen Virusforschung. Progrès en Virologie Médicale 32: 101–14. PMID 3895297. 
  • Porta M, Ayude D, Alguacil J, Jariod M (Feb 2003). "Exploring environmental causes of altered ras effects: fragmentation plus integration?". Molecular Carcinogenesis 36 (2): 45–52. doi:10.1002/mc.10093. PMID 12557259. 
  • Smakman N, Borel Rinkes IH, Voest EE, Kranenburg O (Nov 2005). "Control of colorectal metastasis formation by K-Ras". Biochimica et Biophysica Acta 1756 (2): 103–14. doi:10.1016/j.bbcan.2005.07.001. PMID 16098678. 
  • Castagnola P, Giaretti W (Nov 2005). "Mutant KRAS, chromosomal instability and prognosis in colorectal cancer". Biochimica et Biophysica Acta 1756 (2): 115–25. doi:10.1016/j.bbcan.2005.06.003. PMID 16112461. 
  • Deramaudt T, Rustgi AK (Nov 2005). "Mutant KRAS in the initiation of pancreatic cancer". Biochimica et Biophysica Acta 1756 (2): 97–101. doi:10.1016/j.bbcan.2005.08.003. PMID 16169155. 
  • Pretlow TP, Pretlow TG (Nov 2005). "Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer?". Biochimica et Biophysica 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 Biomarkers 1 (2-3): 177–82. PMID 17192038. 
  • Domagała P, Hybiak J, Sulżyc-Bielicka V, Cybulski C, Ryś J, Domagała W (Nov 2012). "KRAS mutation testing in colorectal cancer as an example of the pathologist's role in personalized targeted therapy: a practical approach". Polish Journal of Pathology 63 (3): 145–64. doi:10.5114/PJP.2012.31499. PMID 23161231. 

External links

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