V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, also known as KRAS, is a protein which in humans is encoded by the KRAS gene. 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. When mutated, KRAS is a oncogene. 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.
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, the unbound KRAS is released from the GEF and quickly re-binds available GTP or GDP present in the cytosol. Since GTP is substantially more abundant than GDP, this usually results in KRAS activation.
Other members of the Ras family include: HRAS, RRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.
This gene is a Kirsten ras oncogene homolog from the mammalian ras gene family. A single amino acid 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 and cardio-facio-cutaneous syndrome.
Somatic KRAS mutations are found at high rates in Leukemias, colon cancer, pancreatic cancer and lung cancer. KRAS mutation is predictive of response to panitumumab and cetuximab therapy in colorectal cancer. 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—a protein that transmits growth signals from EGFR—which occur in 40% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to Erbitux or Vectibix.
Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in the New England Journal of Medicine 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.
KRAS mutational analysis is commercially available from a number of laboratories (see list of clinical labs in the external links section).
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.
KRAS has been shown to interact with C-Raf, RASSF2, PIK3CG and RALGDS.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Schubbert S, Zenker M, Rowe SL, et al. (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405.
- ^ Niihori T, Aoki Y, Narumi Y, et al. (2006). "Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome". Nat. Genet. 38 (3): 294–6. doi:10.1038/ng1749. PMID 16474404.
- ^ 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. PMID 2648401.
- ^ 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.
- ^ Tam IY, Chung LP, Suen WS, et al. (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.
- ^ Lièvre A, Bachet JB, Le Corre D, et al. (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.
- ^ 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). http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/943.
- ^ 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.
- ^ 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.
- ^ OncoGenetics.Org (July 2009). "FDA updates Vectibix and Erbitux labels with KRAS testing info". OncoGenetics.Org. http://www.oncogenetics.org/web/fda-updates-vectibix-and-erbitux-labels-with-kras-testing-info. Retrieved 2009-07-20.
- ^ a b Li, W; Han M, Guan K L (Apr. 2000). "The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf". Genes Dev. (UNITED STATES) 14 (8): 895–900. ISSN 0890-9369. PMID 10783161.
- ^ 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". J. Biol. Chem. (UNITED STATES) 275 (38): 29788–93. doi:10.1074/jbc.M001378200. ISSN 0021-9258. PMID 10882715.
- ^ Vos, Michele D; Ellis Chad A, Elam Candice, Ulku Aylin S, Taylor Barbara J, Clark Geoffrey J (Jul. 2003). "RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor". J. Biol. Chem. (United States) 278 (30): 28045–51. doi:10.1074/jbc.M300554200. ISSN 0021-9258. PMID 12732644.
- ^ 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". Eur. J. Biochem. (GERMANY) 266 (1): 70–82. doi:10.1046/j.1432-1327.1999.00815.x. ISSN 0014-2956. PMID 10542052.
- ^ Spaargaren, M; Bischoff J R (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". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 91 (26): 12609–13. doi:10.1073/pnas.91.26.12609. ISSN 0027-8424. PMID 7809086.
- Kahn S, Yamamoto F, Almoguera C, et al. (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, et al. (2007). "Detection of a K-ras mutation in urine of patients with colorectal cancer.". Cancer biomarkers : section a of Disease markers 1 (2-3): 177–82. PMID 17192038.