Skip to main content
SpringerLink
Log in

Mutational Activation of KRAS and BRAF in Colorectal Cancer

  • Chapter
  • First Online:
Molecular Pathogenesis of Colorectal Cancer

Abstract

The failure of farnesyltransferase inhibitors to show antitumor activity against KRAS-mutant malignancies diminished enthusiasm for efforts to develop anti-Ras inhibitors for cancer treatment. However, two recent developments have rekindled interest in these endeavors. First, genome-wide exome sequencing verified that mutational activation of the KRAS gene is the most prevalent oncogene mutation in colorectal cancer (CRC). Second, a major step toward the application of personalized medicine for CRC was taken when mutant KRAS was established as a prognostic marker for resistance to epidermal growth factor receptor monoclonal antibody therapy. Thus, there is renewed and considerable interest in understanding the role of KRAS mutation in CRC progression and growth and in developing pharmacologic approaches for blocking aberrant K-Ras protein function for CRC treatment. Since the K-Ras protein itself is considered “undruggable,” current strategies to develop anti-K-Ras inhibitors have focused on antagonists of K-Ras downstream effector signaling. The frequent mutational activation of BRAF, which is mutually with KRAS activation, suggests that the encoded B-Raf serine/threonine kinase and activation of the ERK mitogen-activated protein kinase cascade is a key driver of mutant K-Ras-dependent CRC growth. In this review, we summarize the importance of mutant K-Ras and B-Raf in CRC growth and current efforts in targeting the Raf-MEK-ERK cascade for CRC treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahearn IM, Haigis K, Bar-Sagi D et al (2011) Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol 13(1):39–51. doi:10.1038/nrm3255

    Article  PubMed  CAS  Google Scholar 

  • Allegra CJ, Jessup JM, Somerfield MR et al (2009) American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27(12):2091–2096

    Article  PubMed  Google Scholar 

  • Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634. doi:10.1200/JCO.2007.14.7116

    Article  PubMed  CAS  Google Scholar 

  • Andreyev HJ, Norman AR, Cunningham D et al (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85(5):692–696

    Article  PubMed  CAS  Google Scholar 

  • Babij C, Zhang Y, Kurzeja RJ et al (2011) STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res 71(17):5818–5826

    Article  PubMed  CAS  Google Scholar 

  • Balmanno K, Chell SD, Gillings AS et al (2009) Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer 125(10):2332–2341

    Article  PubMed  CAS  Google Scholar 

  • Bandyopadhyay S, Chiang CY, Srivastava J et al (2010) A human MAP kinase interactome. Nat Methods 7(10):801–805

    Article  PubMed  CAS  Google Scholar 

  • Barbie DA, Tamayo P, Boehm JS et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108–112

    Article  PubMed  CAS  Google Scholar 

  • Bergo MO, Ambroziak P, Gregory C et al (2002) Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol Cell Biol 22(1):171–181

    Article  PubMed  CAS  Google Scholar 

  • Bergo MO, Gavino BJ, Hong C et al (2004) Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J Clin Invest 113(4):539–550. doi:10.1172/JCI18829

    PubMed  CAS  Google Scholar 

  • Bermudez O, Pages G, Gimond C (2010) The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol 299(2):C189–C202. doi:10.1152/ajpcell.00347.2009

    Article  PubMed  CAS  Google Scholar 

  • Berndt N, Hamilton AD, Sebti SM (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11(11):775–791. doi:10.1038/nrc3151

    Article  PubMed  CAS  Google Scholar 

  • Bivona TG, Quatela SE, Bodemann BO et al (2006) PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol Cell 21(4):481–493. doi:10.1016/j.molcel.2006.01.012

    Article  PubMed  CAS  Google Scholar 

  • Blum R, Cox AD, Kloog Y (2008) Inhibitors of chronically active ras: potential for treatment of human malignancies. Recent Pat Anticancer Drug Discov 3(1):31–47

    Article  PubMed  CAS  Google Scholar 

  • Bodemann BO, White MA (2008) Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nat Rev Cancer 8(2):133–140. doi:10.1038/nrc2296

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Brown MD, Sacks DB (2009) Protein scaffolds in MAP kinase signalling. Cell Signal 21(4):462–469. doi:10.1016/j.cellsig.2008.11.013

    Article  PubMed  CAS  Google Scholar 

  • Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337. doi:10.1038/nature11252

    Article  CAS  Google Scholar 

  • Cejas P, Lopez-Gomez M, Aguayo C et al (2009) KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS One 4(12):e8199

    Article  PubMed  CAS  Google Scholar 

  • Chan TL, Zhao W, Leung SY et al (2003) BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 63(16):4878–4881

    PubMed  CAS  Google Scholar 

  • Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516

    Article  PubMed  CAS  Google Scholar 

  • Corcoran RB, Ebi H, Turke AB et al (2012) EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2(3):227–235. doi:10.1158/2159-8290.CD-11-0341

    Article  PubMed  CAS  Google Scholar 

  • Cox AD, Der CJ (2010) Ras history: the saga continues. Small GTPases 1(1):2–27

    Article  PubMed  Google Scholar 

  • Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345. doi:10.1056/NEJMoa033025

    Article  PubMed  CAS  Google Scholar 

  • Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954

    Article  PubMed  CAS  Google Scholar 

  • Davies BR, Logie A, McKay JS et al (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 6(8):2209–2219

    Article  PubMed  CAS  Google Scholar 

  • de la Vega M, Burrows JF, Johnston JA (2011) Ubiquitination: added complexity in Ras and Rho family GTPase function. Small GTPases 2(4):192–201. doi:10.4161/sgtp.2.4.16707

    Article  PubMed  Google Scholar 

  • De Roock W, Fieuws S, Biesmans B et al (2009, Abstract 289) DUSP expression as a predictor of outcome after cetuximab treatment in Kras wild type and mutant colorectal tumors. Gastrointestinal cancers symposium of the American Society of Clinical Oncology, San Francisco, 22–24 Jan 2009

    Google Scholar 

  • De Roock W, Claes B, Bernasconi D et al (2010a) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762

    Article  PubMed  CAS  Google Scholar 

  • De Roock W, Claes B, Bernasconi D et al (2010b) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762. doi:10.1016/S1470-2045(10)70130-3

    Article  PubMed  CAS  Google Scholar 

  • De Roock W, Jonker DJ, Di Nicolantonio F et al (2010c) Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304(16):1812–1820

    Article  PubMed  Google Scholar 

  • De Roock W, De Vriendt V, Normanno N et al (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6):594–603

    Article  PubMed  CAS  Google Scholar 

  • Di Nicolantonio F, Martini M, Molinari F et al (2008a) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712

    Article  PubMed  CAS  Google Scholar 

  • Di Nicolantonio F, Martini M, Molinari F et al (2008b) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712. doi:10.1200/JCO.2008.18.0786

    Article  PubMed  CAS  Google Scholar 

  • Dienstmann R, Vilar E, Tabernero J (2011) Molecular predictors of response to chemotherapy in colorectal cancer. Cancer J 17(2):114–126. doi:10.1097/PPO.0b013e318212f844

    Article  PubMed  CAS  Google Scholar 

  • Dienstmann R, Serpico D, Rodon J et al (2012) Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials. Mol Cancer Ther 11(9):2062–2071. doi:10.1158/1535-7163.MCT-12-0290

    Article  PubMed  CAS  Google Scholar 

  • Douillard JY, Cunningham D, Roth AD et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047

    Article  PubMed  CAS  Google Scholar 

  • Ebi H, Corcoran RB, Singh A et al (2011) Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest 121(11):4311–4321. doi:10.1172/JCI57909

    Article  PubMed  CAS  Google Scholar 

  • Edkins S, O’Meara S, Parker A et al (2006) Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther 5(8):928–932

    Article  PubMed  CAS  Google Scholar 

  • Engelman JA, Chen L, Tan X et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14(12):1351–1356

    Article  PubMed  CAS  Google Scholar 

  • Esteban LM, Vicario-Abejon C, Fernandez-Salguero P et al (2001) Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol Cell Biol 21(5):1444–1452. doi:10.1128/MCB.21.5.1444-1452.2001

    Article  PubMed  CAS  Google Scholar 

  • Farr CJ, Marshall CJ, Easty DJ et al (1988) A study of ras gene mutations in colonic adenomas from familial polyposis coli patients. Oncogene 3(6):673–678

    PubMed  CAS  Google Scholar 

  • Fearon ER (2011a) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507. doi:10.1146/annurev-pathol-011110-130235

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER (2011b) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767

    Article  PubMed  CAS  Google Scholar 

  • Fehrenbacher N, Bar-Sagi D, Philips M (2009) Ras/MAPK signaling from endomembranes. Mol Oncol 3(4):297–307

    Article  PubMed  CAS  Google Scholar 

  • Flaherty KT, Infante JR, Daud A et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. doi:10.1056/NEJMoa1210093

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Giacchetti S, Perpoint B, Zidani R et al (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18(1):136–147

    PubMed  CAS  Google Scholar 

  • Gonzalez-Garcia A, Pritchard CA, Paterson HF et al (2005) RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7(3):219–226. doi:10.1016/j.ccr.2005.01.029

    Article  PubMed  CAS  Google Scholar 

  • Guerrero S, Casanova I, Farre L et al (2000) K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res 60(23):6750–6756

    PubMed  CAS  Google Scholar 

  • Gupta S, Ramjaun AR, Haiko P et al (2007) Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129(5):957–968. doi:10.1016/j.cell.2007.03.051

    Article  PubMed  CAS  Google Scholar 

  • Gysin S, Salt M, Young A et al (2011) Therapeutic strategies for targeting ras proteins. Genes Cancer 2(3):359–372

    Article  PubMed  CAS  Google Scholar 

  • Haigis KM, Kendall KR, Wang Y et al (2008) Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet 40(5):600–608

    Article  PubMed  CAS  Google Scholar 

  • Hao H, Muniz-Medina VM, Mehta H et al (2007) Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. Mol Cancer Ther 6(8):2220–2229. doi:10.1158/1535-7163.MCT-06-0728

    Article  PubMed  CAS  Google Scholar 

  • Hatzivassiliou G, Song K, Yen I et al (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464(7287):431–435

    Article  PubMed  CAS  Google Scholar 

  • Hatzivassiliou G, Liu B, O’Brien C et al (2012) ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther. doi:10.1158/1535-7163.MCT-11-1010

    PubMed  Google Scholar 

  • Heid I, Lubeseder-Martellato C, Sipos B et al (2011) Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology 141(2):719–730, 730. e1–7. doi: 10.1053/j.gastro.2011.04.043

    Google Scholar 

  • Heidorn SJ, Milagre C, Whittaker S et al (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140(2):209–221. doi:10.1016/j.cell.2009.12.040

    Article  PubMed  CAS  Google Scholar 

  • Hoeflich KP, Herter S, Tien J et al (2009) Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res 69(7):3042–3051

    Article  PubMed  CAS  Google Scholar 

  • Ikuta S, Edamatsu H, Li M et al (2008) Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Cancer Res 68(1):64–72. doi:10.1158/0008-5472.CAN-07-3245

    Article  PubMed  CAS  Google Scholar 

  • Imamura Y, Morikawa T, Liao X et al (2012) Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res 18(17):4753–4763. doi:10.1158/1078-0432.CCR-11-3210

    Article  PubMed  CAS  Google Scholar 

  • Irahara N, Baba Y, Nosho K et al (2010) NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol 19(3):157–163

    Article  PubMed  CAS  Google Scholar 

  • Janakiraman M, Vakiani E, Zeng Z et al (2010) Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res 70(14):5901–5911

    Article  PubMed  CAS  Google Scholar 

  • Janssen KP, Alberici P, Fsihi H et al (2006) APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131(4):1096–1109

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Article  PubMed  Google Scholar 

  • Jhawer M, Goel S, Wilson AJ et al (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68(6):1953–1961

    Article  PubMed  CAS  Google Scholar 

  • Johnson L, Greenbaum D, Cichowski K et al (1997) K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev 11(19):2468–2481

    Article  PubMed  CAS  Google Scholar 

  • Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765. doi:10.1056/NEJMoa0804385

    Article  PubMed  CAS  Google Scholar 

  • Kissil JL, Walmsley MJ, Hanlon L et al (2007) Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 67(17):8089–8094. doi:10.1158/0008-5472.CAN-07-2300

    Article  PubMed  CAS  Google Scholar 

  • Koera K, Nakamura K, Nakao K et al (1997) K-ras is essential for the development of the mouse embryo. Oncogene 15(10):1151–1159. doi:10.1038/sj.onc.1201284

    Article  PubMed  CAS  Google Scholar 

  • Kopetz S, Desai J, Chan E et al (2010) PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. ASCO Meeting Abstracts no 28(15 suppl):3534

    Google Scholar 

  • Laurent-Puig P, Cayre A, Manceau G et al (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27(35):5924–5930. doi:10.1200/JCO.2008.21.6796

    Article  PubMed  CAS  Google Scholar 

  • Li W, Zhu T, Guan KL (2004) Transformation potential of Ras isoforms correlates with activation of phosphatidylinositol 3-kinase but not ERK. J Biol Chem 279(36):37398–37406. doi:10.1074/jbc.M405730200

    Article  PubMed  CAS  Google Scholar 

  • Li M, Edamatsu H, Kitazawa R et al (2009) Phospholipase Cepsilon promotes intestinal tumorigenesis of Apc(Min/+) mice through augmentation of inflammation and angiogenesis. Carcinogenesis 30(8):1424–1432

    Article  PubMed  CAS  Google Scholar 

  • Lievre 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):3992–3995

    Article  PubMed  CAS  Google Scholar 

  • Lievre A, Bachet JB, Boige V et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26(3):374–379

    Article  PubMed  CAS  Google Scholar 

  • Lim KH, Counter CM (2005) Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 8(5):381–392. doi:10.1016/j.ccr.2005.10.014

    Article  PubMed  CAS  Google Scholar 

  • Lim KH, O’Hayer K, Adam SJ et al (2006) Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol 16(24):2385–2394

    Article  PubMed  CAS  Google Scholar 

  • Liu M, Sjogren AK, Karlsson C et al (2010) Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proc Natl Acad Sci U S A 107(14):6471–6476. doi:10.1073/pnas.0908396107

    Article  PubMed  CAS  Google Scholar 

  • Luo J, Emanuele MJ, Li D et al (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137(5):835–848

    Article  PubMed  CAS  Google Scholar 

  • Luo F, Ye H, Hamoudi R et al (2010) K-ras exon 4A has a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation. J Pathol 220(5):542–550. doi:10.1002/path.2672

    Article  PubMed  CAS  Google Scholar 

  • Malliri A, van der Kammen RA, Clark K et al (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417(6891):867–871. doi:10.1038/nature00848

    Article  PubMed  CAS  Google Scholar 

  • Malliri A, Rygiel TP, van der Kammen RA et al (2006) The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. J Biol Chem 281(1):543–548

    Article  PubMed  CAS  Google Scholar 

  • Mamane Y, Petroulakis E, LeBacquer O et al (2006) mTOR, translation initiation and cancer. Oncogene 25(48):6416–6422

    Article  PubMed  CAS  Google Scholar 

  • Marais R, Light Y, Paterson HF et al (1997) Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 272(7):4378–4383

    Article  PubMed  CAS  Google Scholar 

  • Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361(25):2449–2460. doi:10.1056/NEJMra0804588

    Article  PubMed  CAS  Google Scholar 

  • Martin TD, Samuel JC, Routh ED et al (2011) Activation and involvement of Ral GTPases in colorectal cancer. Cancer Res 71(1):206–215

    Article  PubMed  CAS  Google Scholar 

  • Mason CS, Springer CJ, Cooper RG et al (1999) Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 18(8):2137–2148

    Article  PubMed  CAS  Google Scholar 

  • Matallanas D, Birtwistle M, Romano D et al (2011) Raf family kinases: old dogs have learned new tricks. Genes Cancer 2(3):232–260. doi:10.1177/1947601911407323

    Article  PubMed  CAS  Google Scholar 

  • McFall A, Ulku A, Lambert QT et al (2001) Oncogenic Ras blocks anoikis by activation of a novel effector pathway independent of phosphatidylinositol 3-kinase. Mol Cell Biol 21(16):5488–5499. doi:10.1128/MCB.21.16.5488-5499.2001

    Article  PubMed  CAS  Google Scholar 

  • Michaelson JS, Cho S, Browning B et al (2005) Tweak induces mammary epithelial branching morphogenesis. Oncogene 24(16):2613–2624. doi:10.1038/sj.onc.1208208

    Article  PubMed  CAS  Google Scholar 

  • Mirzoeva OK, Das D, Heiser LM et al (2009) Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 69(2):565–572

    Article  PubMed  CAS  Google Scholar 

  • Montagut C, Settleman J (2009) Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 283(2):125–134

    Article  PubMed  CAS  Google Scholar 

  • Neel NF, Martin TD, Stratford JK et al (2011) The RalGEF-Ral effector signaling network: the road less traveled for anti-Ras drug discovery. Genes Cancer 2(3):275–287. doi:10.1177/1947601911407329

    Article  PubMed  CAS  Google Scholar 

  • Oberholzer PA, Kee D, Dziunycz P et al (2012) RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 30(3):316–321. doi:10.1200/JCO.2011.36.7680

    Article  PubMed  CAS  Google Scholar 

  • Ong CC, Jubb AM, Haverty PM et al (2011) Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci U S A 108(17):7177–7182. doi:10.1073/pnas.1103350108

    Article  PubMed  CAS  Google Scholar 

  • Parsons DW, Wang TL, Samuels Y et al (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436(7052):792

    Article  PubMed  CAS  Google Scholar 

  • Patek CE, Arends MJ, Rose L et al (2008) The pro-apoptotic K-Ras 4A proto-oncoprotein does not affect tumorigenesis in the ApcMin/+ mouse small intestine. BMC Gastroenterol 8:24. doi:10.1186/1471-230X-8-24

    Article  PubMed  CAS  Google Scholar 

  • Paz A, Haklai R, Elad-Sfadia G et al (2001) Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20(51):7486–7493. doi:10.1038/sj.onc.1204950

    Article  PubMed  CAS  Google Scholar 

  • Plowman SJ, Williamson DJ, O’Sullivan MJ et al (2003) While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable. Mol Cell Biol 23(24):9245–9250

    Article  PubMed  CAS  Google Scholar 

  • Plowman SJ, Berry RL, Bader SA et al (2006) K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. J Exp Clin Cancer Res 25(2):259–267

    PubMed  CAS  Google Scholar 

  • Potenza N, Vecchione C, Notte A et al (2005) Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep 6(5):432–437. doi:10.1038/sj.embor.7400397

    Article  PubMed  CAS  Google Scholar 

  • Poulikakos PI, Zhang C, Bollag G et al (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464(7287):427–430

    Article  PubMed  CAS  Google Scholar 

  • Prahallad A, Sun C, Huang S et al (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483(7387):100–103. doi:10.1038/nature10868

    Article  PubMed  CAS  Google Scholar 

  • Prasad SS, Baillie DL (1989) Evolutionarily conserved coding sequences in the dpy-20-unc-22 region of Caenorhabditis elegans. Genomics 5(2):185–198

    Article  PubMed  CAS  Google Scholar 

  • Pratilas CA, Taylor BS, Ye Q et al (2009) (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A 106(11):4519–4524

    Article  PubMed  CAS  Google Scholar 

  • Pretlow TP, Pretlow TG (2005) Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer? Biochim Biophys Acta 1756(2):83–96

    PubMed  CAS  Google Scholar 

  • Price TJ, Hardingham JE, Lee CK et al (2011) Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 29(19):2675–2682

    Article  PubMed  CAS  Google Scholar 

  • Rajagopalan H, Bardelli A, Lengauer C et al (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418(6901):934. doi:10.1038/418934a

    Article  PubMed  CAS  Google Scholar 

  • Rinehart J, Adjei AA, Lorusso PM et al (2004) Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22(22):4456–4462

    Article  PubMed  CAS  Google Scholar 

  • Roth AD, Tejpar S, Delorenzi M et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol 28(3):466–474

    Article  PubMed  CAS  Google Scholar 

  • Saltz LB, Meropol NJ, Loehrer PJ Sr et al (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22(7):1201–1208. doi:10.1200/JCO.2004.10.182

    Article  PubMed  CAS  Google Scholar 

  • Samowitz WS, Sweeney C, Herrick J et al (2005) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65(14):6063–6069

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554. doi:10.1126/science.1096502

    Article  PubMed  CAS  Google Scholar 

  • Santini D, Loupakis F, Vincenzi B et al (2008) High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist 13(12):1270–1275

    Article  PubMed  CAS  Google Scholar 

  • Saridaki Z, Papadatos-Pastos D, Tzardi M et al (2010) BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome. Br J Cancer 102(12):1762–1768

    Article  PubMed  CAS  Google Scholar 

  • Scholl C, Frohling S, Dunn IF et al (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137(5):821–834

    Article  PubMed  CAS  Google Scholar 

  • Shalom-Feuerstein R, Cooks T, Raz A et al (2005) Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells. Cancer Res 65(16):7292–7300. doi:10.1158/0008-5472.CAN-05-0775

    Article  PubMed  CAS  Google Scholar 

  • Shimizu K, Goldfarb M, Suard Y et al (1983) Three human transforming genes are related to the viral ras oncogenes. Proc Natl Acad Sci U S A 80(8):2112–2116

    Article  PubMed  CAS  Google Scholar 

  • Shirasawa S, Furuse M, Yokoyama N et al (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260(5104):85–88

    Article  PubMed  CAS  Google Scholar 

  • Siegel R, Ward E, Brawley O et al (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236. doi:10.3322/caac.20121

    Article  PubMed  Google Scholar 

  • Sjoblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314(5797):268–274. doi:10.1126/science.1133427

    Article  PubMed  CAS  Google Scholar 

  • Sjogren AK, Andersson KM, Liu M et al (2007) GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer. J Clin Invest 117(5):1294–1304. doi:10.1172/JCI30868

    Article  PubMed  CAS  Google Scholar 

  • Solit DB, Garraway LA, Pratilas CA et al (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439(7074):358–362

    Article  PubMed  CAS  Google Scholar 

  • Souglakos J, Philips J, Wang R et al (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101(3):465–472

    Article  PubMed  CAS  Google Scholar 

  • Su F, Viros A, Milagre C et al (2012) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366(3):207–215. doi:10.1056/NEJMoa1105358

    Article  PubMed  CAS  Google Scholar 

  • Takayama T, Ohi M, Hayashi T et al (2001) Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis. Gastroenterology 121(3):599–611

    Article  PubMed  CAS  Google Scholar 

  • Tol J, Nagtegaal ID, Punt CJ (2009) BRAF mutation in metastatic colorectal cancer. N Engl J Med 361(1):98–99

    Article  PubMed  CAS  Google Scholar 

  • Tsai J, Lee JT, Wang W et al (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 105(8):3041–3046

    Article  PubMed  CAS  Google Scholar 

  • Udell CM, Rajakulendran T, Sicheri F et al (2011) Mechanistic principles of RAF kinase signaling. Cell Mol Life Sci 68(4):553–565. doi:10.1007/s00018-010-0520-6

    Article  PubMed  CAS  Google Scholar 

  • Vakiani E, Solit DB (2011) KRAS and BRAF: drug targets and predictive biomarkers. J Pathol 223(2):219–229

    Article  PubMed  CAS  Google Scholar 

  • Vakiani E, Yantiss RK (2009) Pathologic features and biologic importance of colorectal serrated polyps. Adv Anat Pathol 16(2):79–91

    Article  PubMed  CAS  Google Scholar 

  • Vakiani E, Janakiraman M, Shen R et al (2012) Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 30(24):2956–2962. doi:10.1200/JCO.2011.38.2994

    Article  PubMed  CAS  Google Scholar 

  • Van Cutsem E, Kohne CH, Lang I et al (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15):2011–2019

    Article  PubMed  CAS  Google Scholar 

  • Velho S, Oliveira C, Ferreira A et al (2005) The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 41(11):1649–1654

    Article  PubMed  CAS  Google Scholar 

  • Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294(5545):1299–1304

    Article  PubMed  CAS  Google Scholar 

  • Vigil D, Cherfils J, Rossman KL et al (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nature reviews. Cancer 10(12):842–857. doi:10.1038/nrc2960

    PubMed  CAS  Google Scholar 

  • Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532

    Article  PubMed  CAS  Google Scholar 

  • Wahlstrom AM, Cutts BA, Liu M et al (2008) Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease. Blood 112(4):1357–1365. doi:10.1182/blood-2007-06-094060

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Van Becelaere K, Jiang P et al (2005) A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040. Neoplasia 7(4):336–347

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Ngo VN, Marani M et al (2010) Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells. Oncogene 29(33):4658–4670. doi:10.1038/onc.2010.218

    Article  PubMed  CAS  Google Scholar 

  • Wee S, Jagani Z, Xiang KX et al (2009) PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 69(10):4286–4293

    Article  PubMed  CAS  Google Scholar 

  • Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118(Pt 5):843–846. doi:10.1242/jcs.01660

    Article  PubMed  CAS  Google Scholar 

  • Wilson PM, Labonte MJ, Lenz HJ (2010) Molecular markers in the treatment of metastatic colorectal cancer. Cancer J 16(3):262–272. doi:10.1097/PPO.0b013e3181e07738

    Article  PubMed  CAS  Google Scholar 

  • Wong R, Cunningham D (2008) Using predictive biomarkers to select patients with advanced colorectal cancer for treatment with epidermal growth factor receptor antibodies. J Clin Oncol 26(35):5668–5670

    Article  PubMed  CAS  Google Scholar 

  • Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113. doi:10.1126/science.1145720

    Article  PubMed  CAS  Google Scholar 

  • Yeh JJ, Routh ED, Rubinas T et al (2009) KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. Mol Cancer Ther 8(4):834–843

    Article  PubMed  CAS  Google Scholar 

  • Zhang YJ, Tian XQ, Sun DF et al (2009) Combined inhibition of MEK and mTOR signaling inhibits initiation and progression of colorectal cancer. Cancer Invest 27(3):273–285

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Vogt PK (2008) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A 105(7):2652–2657. doi:10.1073/pnas.0712169105

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27599, USA

    Katherine H. Pedone, Jennifer L. Sells & Channing J. Der

Authors
  1. Katherine H. Pedone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer L. Sells
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Channing J. Der
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine H. Pedone .

Editor information

Editors and Affiliations

  1. Molecular Pathology Unit, Harvard Medical School, Charlestown, Massachusetts, USA

    Kevin M. Haigis, Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Pedone, K.H., Sells, J.L., Der, C.J. (2013). Mutational Activation of KRAS and BRAF in Colorectal Cancer. In: Haigis, Ph.D., K. (eds) Molecular Pathogenesis of Colorectal Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8412-7_5

Download citation

Publish with us

Policies and ethics

Search

Navigation