The KRAS gene (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogene that encodes a small GTPase transductor protein called KRAS. KRAS is involved in the regulation of cell division as a result of its ability to relay external signals to the cell nucleus. Activating mutations in the KRAS gene impair the ability of the KRAS protein to switch between active and inactive states, leading to cell transformation and increased resistance to chemotherapy and biological therapies targeting epidermal growth factor receptors. This review highlights some of the features of the KRAS gene and the KRAS protein and summarizes current knowledge of the mechanism of KRAS gene regulation. It also underlines the importance of activating mutations in the KRAS gene in relation to carcinogenesis and their importance as diagnostic biomarkers, providing clues regarding human cancer patients' prognosis and indicating potential therapeutic approaches.

Laboratory of Experimental Medicine Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University and University Hospital 775 20 Olomouc Czech Republic

See more in PubMed

Chang EH, Gonda MA, Ellis RW, et al. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proceedings of the National Academy of Sciences of the United States of America. 1982;79(16):4848–4852. PubMed PMC

Der CJ, Cooper GM. Altered gene products are associated with activation of cellular rask genes in human lung and colon carcinomas. Cell. 1983;32(1):201–208. PubMed

Parada LF, Weinberg RA. Presence of a Kirsten murine sarcoma virus ras oncogene in cells transformed by 3-methylcholanthrene. Molecular & Cellular Biology. 1983;3(12):2298–2301. PubMed PMC

Esser D, Bauer B, Wolthuis RMF, Wittinghofer A, Cool RH, Bayer P. Structure determination of the ras-binding domain of the Ral-specific guanine nucleotide exchange factor Rlf. Biochemistry. 1998;37(39):13453–13462. PubMed

Zuber J, Tchernitsa OI, Hinzmann B, et al. A genome-wide survey of RAS transformation targets. Nature Genetics. 2000;24(2):144–152. PubMed

Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. Journal of Cell Science. 2005;118(5):843–846. PubMed

Paduch M, Jeleń F, Otlewski J. Structure of small G proteins and their regulators. Acta Biochimica Polonica. 2001;48(4):829–850. PubMed

McGrath JP, Capon DJ, Smith DH. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature. 1983;304(5926):501–506. PubMed

Gideon P, John J, Frech M, et al. Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity. Molecular and Cellular Biology. 1992;12(5):2050–2056. PubMed PMC

Giglione C, Parrini MC, Baouz S, Bernardi A, Parmeggiani A. A new function of p120-GTPase-activating protein: prevention of the guanine nucleotide exchange factor-stimulated nucleotide exchange on the active form of Ha-Ras p21. The Journal of Biological Chemistry. 1997;272(40):25128–25134. PubMed

Scheffzek K, Ahmadian MR, Kabsch W, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic ras mutants. Science. 1997;277(5324):333–338. PubMed

Hancock JF, Prior IA. Electron microscopic imaging of Ras signaling domains. Methods. 2005;37(2):165–172. PubMed PMC

Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell. 1989;57(7):1167–1177. PubMed

Rajalingam K, Schreck R, Rapp UR, Albert Š. Ras oncogenes and their downstream targets. Biochimica et Biophysica Acta. 2007;1773(8):1177–1195. PubMed

Thissen JA, Gross JM, Subramanian K, Meyer T, Casey PJ. Prenylation-dependent association of Ki-Ras with microtubules. Evidence for a role in subcellular trafficking. The Journal of Biological Chemistry. 1997;272(48):30362–30370. PubMed

Hingorani SR, Petricoin EF, III, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4(6):437–450. PubMed

Fivaz M, Meyer T. Reversible intracellular translocation of KRAS but not HRas in hippocampal neurons regulated by CCa2+/calmodulin. Journal of Cell Biology. 2005;170(3):429–441. PubMed PMC

Zhang Z, Wang Y, Vikis HG, et al. Wildtype KRAS2 can inhibit lung carcinogenesis in mice. Nature Genetics. 2001;29(1):25–33. PubMed

McCoy MS, Toole JJ, Cunningham JM, et al. Characterization of a human colon/lung carcinoma oncogene. Nature. 1983;302(5903):79–81. PubMed

Kranenburg O. The KRAS oncogene: past, present, and future. Biochimica et Biophysica Acta. 2005;1756(2):81–82. PubMed

Hegi ME, Devereux TR, Dietrich WF, et al. Allelotype analysis of mouse long carcinomas reveals frequent allelic losses on chromosome 4 and an association between allelic imbalances on chromosome 6 and K-ras activation. Cancer Research. 1994;54(23):6257–6264. PubMed

Barbacid M. Ras genes. Annual Review of Biochemistry. 1987;56:779–827. PubMed

Liao J, Wolfman JC, Wolfman A. K-Ras regulates the steady-state expression of matrix metalloproteinase 2 in fibroblasts. The Journal of Biological Chemistry. 2003;278(34):31871–31878. PubMed

Yan Z, Deng X, Chen M, et al. Oncogenic c-Ki-ras but not oncogenic c-Ha-ras up-regulates CEA expression and disrupts basolateral polarity in colon epithelial cells. The Journal of Biological Chemistry. 1997;272(44):27902–27907. PubMed

McBride OW, Swan DC, Tronick SR, et al. Regional chromosomal localization of N-ras, K-ras-1, K-ras-2 and myb oncogenes in human cells. Nucleic Acids Research. 1983;11(23):8221–8236. PubMed PMC

Popescu NC, Amsbaugh SC, DiPaolo JA. Chromosomal localization of three human ras genes by in situ molecular hybridization. Somatic Cell and Molecular Genetics. 1985;11(2):149–155. PubMed

Carta C, Pantaleoni F, Bocchinfuso G, et al. Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. American Journal of Human Genetics. 2006;79(1):129–135. PubMed PMC

Takeuchi S, Bartram CR, Miller CW, et al. Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1. Blood. 1996;87(8):3368–3374. PubMed

Li J, Zhang Z, Dai Z, et al. LOH of chromosome 12p correlates with KRAS2 mutation in non-small cell lung cancer. Oncogene. 2003;22(8):1243–1246. PubMed PMC

Ogino S, Kawasaki T, Brahmandam M, et al. Sensitive sequencing method for KRAS mutation detection by pyrosequencing. Journal of Molecular Diagnostics. 2005;7(3):413–421. PubMed PMC

Khanifar E, Ward PM. Modified mutagenic PCR-RFLP and PCR-ASO methods for the detection of KRAS codon 12 and 13 mutations in colorectal cancer. Journal of Molecular Diagnostics. 2008;10(6):p. 599.

Moul JW, Theune SM, Chang EH. Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization. Genes Chromosomes & Cancer. 1992;5(2):109–118. PubMed

Zhu D-B, Xing D, Li X, Zhang L. Rapid detection of K-ras oncogene point mutation by real-time fluorescence allele-specific amplification. Chemical Journal of Chinese Universities. 2007;28(6):1031–1034.

Park J-H, Kim I-J, Kang HC, et al. Oligonucleotide microarray-based mutation detection of the K-ras gene in colorectal cancers with use of competitive DNA hybridization. Clinical Chemistry. 2004;50(9):1688–1691. PubMed

Wabuyele MB, Farquar H, Stryjewski W, et al. Approaching real-time molecular diagnostics: single-pair fluorescence resonance energy transfer (spFRET) detection for the analysis of low abundant point mutations in K-ras oncogenes. Journal of the American Chemical Society. 2003;125(23):6937–6945. PubMed

Fernandez-Vega C, Garcia-Olmo DC, Ballesteros MA, Garcia-Olmo D. Development of a simple and sensitive technique for detection of point mutations in the K-ras oncogene. Applied Biochemistry and Biotechnology Part B. 2002;22(2):115–121. PubMed

Albitar M, Wu WC, Feltz E, et al. Simplified reverse dot blot analyses for detecting ras oncogene mutations. Molecular Diagnosis. 1997;2(3):169–176. PubMed

Bentivegna S, Zheng J, Namsaraev E, et al. Rapid identification of somatic mutations in colorectal and breast cancer tissues using mismatch repair detection (MRD) Human Mutation. 2008;29(3):441–450. PubMed

Amicarelli G, Shehi E, Makrigiorgos MG, Adlerstein D. FLAG assay as a novel method for real-time signal generation during PCR: application to detection and genotyping of KRAS codon 12 mutations. Nucleic Acids Research. 2007;35(19, article e131) PubMed PMC

Amicarelli G, Adlerstein D, Shehi E, Wang F, Makrigiorgos GM. Genotype-specific signal generation based on digestion of 3-way DNA junctions: application to KRAS variation detection. Clinical Chemistry. 2006;52(10):1855–1863. PubMed

Ekstrom PO, Bjorheim J. Evaluation of sieving matrices used to separate alleles by cycling temperature capillary electrophoresis. Electrophoresis. 2006;27(10):1878–1885. PubMed

Bjorheim J, Minarik M, Gaudernack G, Ekstrom PO. Mutation detection in KRAS exon 1 by constant denaturant capillary electrophoresis in 96 parallel capillaries. Analytical Biochemistry. 2002;304(2):200–205. PubMed

Minarik M, Minarikova L, Hrabikova M, Minarikova P, Hrabal P, Zavoral M. Application of cycling gradient capillary electrophoresis to detection of APC, K-ras, and DCC point mutations in patients with sporadic colorectal tumors. Electrophoresis. 2004;25(7-8):1016–1021. PubMed

Taylor CF. Mutation scanning using high-resolution melting. Biochemical Society Transactions. 2009;37(2):433–437. PubMed

Zou H, Taylor WR, Harrington JJ, et al. High detection rates of colorectal neoplasia by stool DNA testing with a novel digital melt curve assay. Gastroenterology. 2009;136(2):459–470. PubMed

Bian Y, Matsubayashi H, Pin-Li C, et al. Detecting low-abundance p16 and p53 mutations in pancreatic juice using a novel assay: heteroduplex analysis of limiting dilution PCRs. Cancer Biology and Therapy. 2006;5(10):1392–1399. PubMed

Endo Y, Zhang L, Katashima R, et al. Effect of polymer matrix and glycerol on rapid single-strand conformation polymorphism analysis by capillary and microchip electrophoresis for detection of mutations in K-ras gene. Electrophoresis. 2005;26(17):3380–3386. PubMed

Banerjee SK, Makdisi WF, Weston AP, Campbell DR. A two-step enriched-nested PCR technique enhances sensitivity for detection of codon 12 K-ras mutations in pancreatic adenocarcinoma. Pancreas. 1997;15(1):16–24. PubMed

Lim EH, Zhang S-L, Li J-L, et al. Using whole genome amplification (WGA) of low-volume biopsies to assess the prognostic role of EGFR, KRAS, p53, and CMET mutations in advanced-stage non-small cell lung cancer (NSCLC) Journal of Thoracic Oncology. 2009;4(1):12–21. PubMed

Li J, Makrigiorgos GM. COLD-PCR: a new platform for highly improved mutation detection in cancer and genetic testing. Biochemical Society Transactions. 2009;37(2):427–432. PubMed

Beau-Faller M, Legrain M, Voegeli A-C, et al. Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping. British Journal of Cancer. 2009;100(6):985–992. PubMed PMC

Tatsumi K, Mitani Y, Watanabe J, et al. Rapid screening assay for KRAS mutations by the modified smart amplification process. Journal of Molecular Diagnostics. 2008;10(6):520–526. PubMed PMC

Nollau P, Fischer C, Tschentscher P, Wagener C. Enrichment of mutant alleles by chromatographic removal of wild type alleles: a new principle for the detection of alleles with unknown point mutations at excess of wild type alleles. Clinical Chemistry and Laboratory Medicine. 1999;37(9):877–881. PubMed

Newton CR, Graham A, Heptinstall LE, et al. Analysis of any point mutation in DNA. The aplivication refractory mutation system (ARMS) Nucleic Acids Research. 1989;17(7):2503–2516. PubMed PMC

Thelwell N, Millington S, Solinas A, Booth J, Brown T. Mode of action and application of Scorpion primers to mutataon detection. Nucleic Acids Research. 2000;28(19):3752–3761. PubMed PMC

Cogoi S, Xodo LE. G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Research. 2006;34(9):2536–2549. PubMed PMC

Yanagihara M, Ishikawa S, Naito M, Nakajima J, Aburatani H, Hatakeyama M. Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene. Oncogene. 2005;24(38):5878–5887. PubMed

Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–858. PubMed

Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15–20. PubMed

Lai EC. Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation. Nature Genetics. 2002;30(4):363–364. PubMed

Michael MZ, O’Connor SM, Van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Molecular Cancer Research. 2003;1(12):882–891. PubMed

Tam W, Hughes SH, Hayward WS, Besmer P. Avian bic, a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA, cooperates with c-myc in lymphomagenesis and erythroleukemogenesis. Journal of Virology. 2002;76(9):4275–4286. PubMed PMC

Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(9):2999–3004. PubMed PMC

Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901–906. PubMed

Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–854. PubMed

Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 2003;113(1):25–36. PubMed

Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of-target mRNAs. Nature. 2005;433(7027):769–773. PubMed

Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Research. 2004;64(11):3753–3756. PubMed

Goga A, Benz C. Anti-oncomir suppression of tumor phenotypes. Molecular Interventions. 2007;7(4):199–202. PubMed

Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635–647. PubMed

Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clinical Cancer Research. 2007;13(10):2890–2896. PubMed

Anderson MW, Reynolds SH, You M, Maronpot RM. Role of Proto-oncogene activation in carcinogenesis. Environmental Health Perspectives. 1992;98:13–24. PubMed PMC

Bos JL, Fearon ER, Hamilton SR. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327(6120):293–297. PubMed

Downward J. Role of receptor tyrosine kinases in G-protein-coupled receptor regulation of Ras: transactivation or parallel pathways? Biochemical Journal. 2003;376:e9–e10. PubMed PMC

Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nature Reviews Cancer. 2007;7(4):295–308. PubMed

Guerra C, Mijimolle N, Dhawahir A, et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003;4(2):111–120. PubMed

Barbacid M. ras oncogenes: their role in neoplasia. European Journal of Clinical Investigation. 1990;20(3):225–235. PubMed

Rodenhuis S, Slebos RJC. The ras oncogenes in human lung cancer. American Review of Respiratory Disease. 1990;142(6, part 2):S27–S30. PubMed

Clayton SJ, Scott FM, Walker J, et al. K-ras point mutation detection in lung cancer: comparison of two approaches to somatic mutation detection using ARMS allele-specific amplification. Clinical Chemistry. 2000;46(12):1929–1938. PubMed

Marshall CJ. How does p21ras transform cells? Trends in Genetics. 1991;7(3):91–95. PubMed

Serrano M. The tumor suppressor protein p16INK4a. Experimental Cell Research. 1997;237(1):7–13. PubMed

Rengan R, Cengel KA, Hahn SM. Clinical target promiscuity: lessons from ras molecular trials. Cancer and Metastasis Reviews. 2008;27(3):403–414. PubMed

Li D, Firozi PF, Zhang W, et al. DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mutation Research. 2002;513(1-2):37–48. PubMed

Wei S, Liang Z, Gao J, et al. Patterns of K-ras codon 12 and 13 mutations found in pancreatic adenocarcinoma of 30 Chinese patients by microdissection, PCR and direct sequencing. Journal of Gastroenterology and Hepatology. 2005;20(1):67–72. PubMed

Laghi L, Orbetegli O, Bianchi P, et al. Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers. Oncogene. 2002;21(27):4301–4306. PubMed

Hruban RH, van Mansfeld ADM, Offerhaus GJA, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas: a study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. American Journal of Pathology. 1993;143(2):545–554. PubMed PMC

Porta M, Malats N, Guarner L, et al. Association between coffee drinking and K-ras mutations in exocrine pancreatic cancer. Journal of Epidemiology and Community Health. 1999;53(11):702–709. PubMed PMC

Malats N, Porta M, Corominas JM, et al. Ki-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. International Journal of Cancer. 1997;70(6):661–667. PubMed

Morales E, Porta M, Vioque J, et al. Food and nutrient intakes and K-ras mutations in exocrine pancreatic cancer. Journal of Epidemiology and Community Health. 2007;61(7):641–649. PubMed PMC

Bazan V, Agnese V, Corsale S, et al. Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study. Annals of Oncology. 2005;16(supplement 4):iv50–iv55. PubMed

Benhattar J, Saraga E. Molecular genetics of dysplasia in ulcerative colitis. European Journal of Cancer Part A. 1995;31(7-8):1171–1173. PubMed

Otori K, Oda Y, Sugiyama K, et al. High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut. 1997;40(5):660–663. PubMed PMC

Forrester K, Almoguera C, Han K. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 1987;327(6120):298–303. PubMed

Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. The New England Journal of Medicine. 1988;319(9):525–532. PubMed

Kimura K, Nagasaka I, Hoshizima N, et al. No duplicate KRAS mutation is identified on the same allele in gastric or colorectal cancer cells with multiple KRAS mutations. Journal of International Medical Research. 2007;35(4):450–457. PubMed

Al-Mulla F, Going JJ, Sowden ETHH, Winter A, Pickford IR, Birnie GD. Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. Journal of Pathology. 1998;185(2):130–138. PubMed

Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiology Biomarkers and Prevention. 2000;9(11):1193–1197. PubMed

Park J-I, Strock CJ, Ball DW, Nelkin BD. The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway. Molecular and Cellular Biology. 2003;23(2):543–554. PubMed PMC

Ahrendt SA, Decker PA, Alawi EA, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 2001;92(6):1525–1530. PubMed

Broermann P, Junker K, Brandt BH, et al. Trimodality treatment in stage III nonsmall cell lung carcinoma: prognostic impact of K-ras mutations after neoadjuvant therapy. Cancer. 2002;94(7):2055–2062. PubMed

Huncharek M, Muscat J, Geschwind J-F. K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases. Carcinogenesis. 1999;20(8):1507–1510. PubMed

Westra WH, Slebos RJC, Offerhaus GJA, et al. K-ras oncogene activation in lung adenocarcinomas from former smokers: evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer. 1993;72(2):432–438. PubMed

Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of Clinical Oncology. 2005;23(25):5900–5909. PubMed

Hollestelle A, Elstrodt F, Nagel JHA, Kallemeijn WW, Schutte M. Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Molecular Cancer Research. 2007;5(2):195–201. PubMed

Bamford S, Dawson E, Forbes S, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. British Journal of Cancer. 2004;91(2):355–358. PubMed PMC

Uberall I, Kolar Z, Trojanec R, et al. The status and role of ErbB receptors in human cancer. Experimental and Molecular Pathology. 2008;84(2):79–89. PubMed

Hann CL, Brahmer JR. Who should receive epidermal growth factor receptor inhibitors for non-small cell lung cancer and when? Current Treatment Options in Oncology. 2007;8(1):28–37. PubMed

Sugio K, Uramoto H, Ono K, et al. Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. British Journal of Cancer. 2006;94(6):896–903. PubMed PMC

Tam IYS, Chung LP, Suen WS, et al. 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. 2006;12(5):1647–1653. PubMed

Tamura K, Fukuoka M. Gefitinib in non-small cell lung cancer. Expert Opinion on Pharmacotherapy. 2005;6(6):985–993. PubMed

Hotta K, Kiura K, Ueoka H, et al. Effect of gefitinib (‘Iressa’, ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. Lung Cancer. 2004;46(2):255–261. PubMed

Katzel JA, Fanucchi MP, Li Z. Recent advances of novel targeted therapy in non-small cell Lung cancer. Journal of Hematology and Oncology. 2009;2, article 2 PubMed PMC

Demetri GD. Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. Seminars in Oncology. 2001;28(5, supplement 17):19–26. PubMed

Joske DJL. Chronic myeloid leukaemia: the evolution of gene-targeted therapy. Medical Journal of Australia. 2008;189(5):277–282. PubMed

Agarwal A, Eide CA, Harlow A, et al. An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia. 2008;22(12):2269–2272. PubMed

Lievre A, Bachet J-B, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. Journal of Clinical Oncology. 2008;26(3):374–379. PubMed

Giusti RM, Shastri K, Pilaro AM, et al. U.S. food and drug administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clinical Cancer Research. 2008;14(5):1296–1302. PubMed

Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26(10):1626–1634. PubMed

Grana TM, Rusyn EV, Zhou H, Sartor CI, Cox AD. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Research. 2002;62(14):4142–4150. PubMed

Escandell JM, Kaler P, Recio MC, et al. Activated KRAS protects colon cancer cells from cucurbitacin-induced apoptosis: the role of p53 and p21. Biochemical Pharmacology. 2008;76(2):198–207. PubMed PMC

Samouelian V, Maugard CM, Jolicoeur M, et al. Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFβ-RII, KRAS2, TP53 and/or CDNK2A. Cancer Chemotherapy and Pharmacology. 2004;54(6):497–504. PubMed

Rosell R, Gonzalez-Larriba JL, Alberola V, et al. Single-agent paclitaxel by 3-hour infusion in the treatment of non-small cell lung cancer: links between p53 and K-ras gene status and chemosensitivity. Seminars in Oncology. 1995;22(6, supplement 14):12–18. PubMed

Jean GW, Shah SR. Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer. Pharmacotherapy. 2008;28(6):742–754. PubMed

Sirak I, Petera J, Hatlova J, et al. Epidermal growth factor receptor as a predictor of tumor response to preoperative chemoradiation in locally advanced gastric carcinoma. Strahlentherapie und Onkologie. 2008;184(11):592–597. PubMed

Ross PJ, George M, Cunningham D, et al. Inhibition of Kirsten-ras expression in human colorectal cancer using rationally selected Kirsten-ras antisense oligonucleotides. Molecular Cancer Therapeutics. 2001;1(1):29–41. PubMed

Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma. Cancer. 2001;92(3):488–499. PubMed

Konishi T, Huang CL, Adachi M, et al. The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers. International Journal of Oncology. 2000;16(3):501–511. PubMed

Hurwitz H, Saini S. Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse events. Seminars in Oncology. 2006;33(supplement 10):S26–S34. PubMed

Zhang Z, Jiang G, Yang F, Wang J. Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells. Cancer Biology & Therapy. 2006;5(11):1481–1486. PubMed

Tong AW, Zhang Y-A, Cunningham C, Maples P, Nemunaitis J. Potential clinical application of antioncogene ribozymes for human lung cancer. Clinical Lung Cancer. 2001;2(3):220–226. PubMed

Appels NMGM, Beijnen JH, Schellens JHM. Development of farnesyl transferase inhibitors: a review. Oncologist. 2005;10(8):565–578. PubMed

Sousa SF, Fernandes PA, Ramos MJ. Farnesyltransferase inhibitors: a detailed chemical view on an elusive biological problem. Current Medicinal Chemistry. 2008;15(15):1478–1492. PubMed

Breaking boundaries: role of the brain barriers in metastatic process

G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab

A comparison of Direct sequencing, Pyrosequencing, High resolution melting analysis, TheraScreen DxS, and the K-ras StripAssay for detecting KRAS mutations in non small cell lung carcinomas

MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications