BRAF vs RAS oncogenes: Are mutations of the same pathway equal? Differential signalling and therapeutic implications

Oncotarget

Volumn 5, Issue 23, 2014, Pages 11752-11777

  Oikonomou, Eftychia ^a   Koustas, Evangelos ^a   Goulielmaki, Maria ^a   Pintzas, Alexander ^a  

^a INSTITUTE OF BIOLOGY   (Greece)

Author keywords

BRAF vs KRAS; Cancer; Differential signalling; Rational drug combinations to overcome resistance; Targeted therapeutics

Indexed keywords

2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; 2 [4 (1 HYDROXYIMINO 5 INDANYL) 3 (4 PYRIDINYL) 1H PYRAZOL 1 YL]ETHANOL; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; AZD 8055; B RAF KINASE INHIBITOR; BEVACIZUMAB; BINIMETINIB; CETUXIMAB; CHIR 265; COBIMETINIB; DABRAFENIB; ENCORAFENIB; EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY; GDC 0897; IMATINIB; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; N [3 (5 CHLORO 1H PYRROLO[2,3 B]PYRIDINE 3 CARBONYL) 2,4 DIFLUOROPHENYL]PROPANESULFONAMIDE; PANITUMUMAB; PIMASERTIB; PLX 3603; PROTEIN FARNESYLTRANSFERASE INHIBITOR; REFAMETINIB; SELUMETINIB; SORAFENIB; TRAMETINIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VEMURAFENIB; XL 281; ZD 6244; B RAF KINASE;

ANOREXIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; BASAL CELL CARCINOMA; BRAF GENE; CANCER PROGNOSIS; CANCER RESISTANCE; CANCER SURVIVAL; CARCINOGENESIS; CELL AGING; COLORECTAL CANCER; DIARRHEA; DNA SEQUENCE; DRUG EFFICACY; DRUG POTENCY; DRUG RESISTANCE; DRUG RESPONSE; DRUG SAFETY; DRUG SELECTIVITY; DRUG SENSITIZATION; DRUG TARGETING; DRUG TOLERABILITY; ENZYME ACTIVATION; FATIGUE; FEVER; GENE EXPRESSION; GENE MUTATION; HEMATOLOGIC DISEASE; HUMAN; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LUNG ADENOCARCINOMA; LUNG CANCER; LYMPHOMA; MELANOMA; METASTATIC COLORECTAL CANCER; METASTATIC MELANOMA; MICROSATELLITE INSTABILITY; MOLECULARLY TARGETED THERAPY; MOUTH SQUAMOUS CELL CARCINOMA; MULTIPLE MYELOMA; NAUSEA; NEOPLASM; NON SMALL CELL LUNG CANCER; NONHUMAN; ONCOGENE; ONCOGENE H RAS; ONCOGENE K RAS; ONCOGENE N RAS; ONCOGENE RAS; PANCREAS CANCER; PERSONALIZED MEDICINE; RASH; SENESCENCE; SIGNAL TRANSDUCTION; SOLID TUMOR; SQUAMOUS CELL CARCINOMA; THYROID PAPILLARY CARCINOMA; UNSPECIFIED SIDE EFFECT; GENETICS; MUTATION; NEOPLASMS;

GENES, RAS; HUMANS; MUTATION; NEOPLASMS; PROTO-ONCOGENE PROTEINS B-RAF; SIGNAL TRANSDUCTION;

EID: 84919969088     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.2555     Document Type: Article

References (209)

1. Prior IA, Hancock JF. Ras trafficking, localization and compartmentalized signalling. Semin Cell Dev Biol. 2012; 23:145-53.
2. Mercer KE, Pritchard CA. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta. 2003; 1653:25-40.
3. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001; 2:127-37.
4. Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, Zhang XF. Ras Activation of the Raf Kinase: Tyrosine Kinase Recruitment of the MAP Kinase Cascade. Recent Prog Horm Res. 2001; 56:127-55.
5. Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011; 2:344-58.
6. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359:1757-65.
7. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26:1626-34.
8. Edkins S, O'Meara S, Parker A, Stevens C, Reis M, Jones S, Greenman C, Davies H, Dalgliesh G, Forbes S, et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006; 5:928-32.
9. Feig LA, Cooper GM. Relationship among guanine nucleotide exchange, GTP hydrolysis, and transforming potential of mutated ras proteins. Mol Cell Biol. 1988; 8:2472-8.
10. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009; 101:715-21.
11. Janakiraman M, Vakiani E, Zeng Z, Pratilas CA, Taylor BS, Chitale D, Halilovic E, Wilson M, Huberman K, Ricarte Filho JC, et al. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 2010; 70:5901-11.
12. Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008; 40:600-8.
13. Castellano E, Santos E. Functional specificity of ras isoforms: so similar but so different. Genes Cancer. 2011; 2:216-31.
14. Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988; 16:7773-82.
15. Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989; 49:4682-9.
16. Almoquera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988; 53:549-54.
17. Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, HamelinZR, et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005; 4:1649-54.
18. Li HT, Lu YY, An YX, Wang X, Zhao QC. KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer. Oncol Rep. 2011; 25:1691-7.
19. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011; 29:1239-46.
20. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 1999; 18:813-22.
21. Prior IA, Lewis PD, Mattos CA. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012; 75:2457-67.
22. Yarbrough WG, Shores C, Witsell DL, Weissler MC, Fidler ME, Gilmer TM. ras mutations and expression in head and neck squamous cell carcinomas. Laryngoscope. 1994; 104:1337-47.
23. Belinsky SA, Devereux TR, Maronpot RR, Stoner GD, Anderson MW. Relationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumours from A/J mice treated with nitrosamines. Cancer Res. 1989; 49:5305-11.
24. Bishehsari F, Mahdavinia M, Malekzadeh R, Verginelli F, Catalano T, Sotoudeh M, Bazan V, Agnese V, Esposito DL, De Lellis L, et al. Patterns of K-ras mutation in colorectal carcinomas from Iran and Italy (a Gruppo Oncologico dell'Italia Meridionale study): influence of microsatellite instability status and country of origin. Ann Oncol. 2006; 17:vii91-6.
25. Calistri D, Rengucci C, Seymour I, Lattuneddu A, Polifemo AM, Monti F, Saragoni L, Amadori D. Mutation analysis of p53, K-ras, and BRAF genes in colorectal cancer progression. J Cell Physiol. 2005; 204:484-8.
26. Roberts ML, Drosopoulos KG, Vasileiou I, Stricker M, Taoufik E, Maercker C, et al. Microarray analysis of the differential transformation mediated by Kirsten and Harvey Ras oncogenes in a human colorectal adenocarcinoma cell line. Int J Cancer. 2006; 118:616-27.
27. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417:949-54.
28. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002; 62:6997-7000.
29. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW, Sidransky D. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003; 95:625-7.
30. Barault L, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, Lièvre A, Cortet M, Bouvier AM, Rat P, et al. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer. 2008; 122:2255-9.
31. Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, Wolff RK, Slattery ML. Poor survival associated with the BRAF V600E mutation in microsatellitestable colon cancers. Cancer Res. 2005; 65:6063-9.
32. Mitsutake N, Knauf JA, Mitsutake S, Mesa JrC, Zhang L, Fagin JA. Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Res. 2005; 65:2465-73.
33. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002; 418:934.
34. Oikonomou E, Makrodouli E, Evagelidou M, Joyce T, Probert L, Pintzas A. BRAF(V600E) efficient transformation and induction of microsatellite instability versus KRAS(G12V) induction of senescence markers in human colon cancer cells. Neoplasia. 2009; 11:1116-31.
35. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011; 29:1239-46.
36. Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N, Affolter A, Nourry A, Niculescu-Duvaz D, Springer C, et al. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med. 2010; 2:35ra41.
37. Hafsi S, Pezzino FM, Candido S, Ligresti G, Spandidos DA, Soua Z, McCubrey JA, Travali S, Libra M. Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drugresistance. Int J Oncol. 2012; 40:639-44.
38. Weinstein IB, Joe A. Oncogene Addiction. Cancer Res. 2008; 68:3077-80.
39. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Montalto G, Cervello M, Nicoletti F, Fagone P, Malaponte G, Mazzarino MC, et al. Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/ mTOR cascades which alter therapy response. Oncotarget. 2012; 3:954-87.
40. Fujimoto K, Sheng H, Shao J, Beauchamp RD. Transforming growth factor-beta1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells. Exp Cell Res. 2001; 266:239-49.
41. Sumimoto H, Miyagishi M, Miyoshi H, Yamagata S, Shimizu A, Taira K, Kawakami Y. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene. 2004; 23:6031-9.
42. Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, Caiazzo F, Basolo F, Giannini R, Kruhoffer M, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest. 2005; 115:1068-81.
43. Makrodouli E, Oikonomou E, Koc M, Andera L, Sasazuki T, Shirasawa S, Pintzas A. BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study. Mol Cancer. 2011; 10:118.
44. Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 2002; 62:6451-5.
45. Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espín E, Armengol M, Yamamoto H, Hamelin R, Seruca R, et al. BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene. 2003; 22:9192-6.
46. Wang L, Cunningham JM, Winters JL, Guenther JC, French AJ, Boardman LA. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res. 2003; 63:5209-12.
47. Marshall MS. Ras target proteins in eukaryotic cells. FASEB J. 1995; 9:1311-8.
48. Sewing A, Wiseman B, Lloyd AC, Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol. 1997; 17:5588-97.
49. Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol. 1997; 17:5598-611.
50. Kerkhoff E, Rapp UR. Cell cycle targets of Ras/Raf signalling. Oncogene. 1998; 17:1457-62.
51. White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M, Wigler MH. Multiple Ras functions can contribute to mammalian cell transformation. Cell. 1995; 80:533-41.
52. Serrano M, Lin A, McCurrach M, Beach D, Lowe S. Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a. Cell. 1997; 88:593-602.
53. Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006; 10:459-72.
54. Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004; 5:375-87.
55. Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, Campuzano V, Barbacid M. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003; 4:111-20.
56. Konishi H, Karakas B, Abukhdeir AM, Lauring J, Gustin JP, Garay JP, Konishi Y, Gallmeier E, Bachman KE, Park BH. Knock-in of mutant K-ras in nontumorigenic human epithelial cells as a new model for studying K-ras mediated transformation. Cancer Res. 2007; 67:8460-7.
57. Vartanian S, Bentley C, Brauer MJ, Li L, Shirasawa S, Sasazuki T, Kim JS, Haverty P, Stawiski E, Modrusan Z, Waldman T, et al. Identification of mutant K-Ras-dependent phenotypes using a panel of isogenic cell lines. J Biol Chem. 2013; 288:2403-13.
58. Campbell PM, Groehler AL, Lee KM, Ouellette MM, Khazak V, Der CJ. K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res. 2007; 67:2098-106.
59. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001; 410:1111-6.
60. Zhou Y, Rideout WM 3rd, Zi T, Bressel A, Reddypalli S, Rancourt R, Woo JK, Horner JW, Chin L, Chiu MI. Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRASdependent lung adenocarcinomas. Nat Biotechnol. 2010; 28:71-8.
61. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev. 2010; 29:49-60.
62. Pollock CB, Shirasawa S, Sasazuki T, Kolch W, Dhillon AS. Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells. Cancer Res. 2005; 65:1244-50.
63. Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008; 40:600-8.
64. Castellano E, Sheridan C, Thin MZ, Nye E, Spencer-Dene B, Diefenbacher ME, Moore C, Kumar MS, Murillo MM, Grönroos E, et al. Requirement for interaction of PI3-kinase p110a with RAS in lung tumor maintenance. Cancer Cell. 2013; 24:617-30.
65. Wang GM, Wong HY, Konishi H, Blair BG, Abukhdeir AM, Gustin JP, Rosen DM, Denmeade SR, Rasheed Z, Matsui W, et al. Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation. Cancer Res. 2013; 73:3248-61.
66. Kim IJ, Kang HC, Jang SG, Kim K, Ahn SA, Yoon HJ, Yoon SN, Park JG. Oligonucleotide microarray analysis of distinct gene expression patterns in colorectal cancer tissues harboring BRAF and K-ras mutations. Carcinogenesis. 2006; 27:392-404.
67. Kikuchi H, Pino MS, Zeng M, Shirasawa S, Chung DC. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and-2alpha in colon cancer. Cancer Res. 2009; 69:8499-506.
68. Magudia K, Lahoz A, Hall A. K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc. J Cell Biol. 2012; 198:185-94.
69. Cagnol S, Rivard N. Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/ MKP2) resulting in nuclear ERK1/2 inhibition. Oncogene. 2013; 32:564-76.
70. Kemper K Versloot M, Cameron K, Colak S, de Sousa E, Melo F, de Jong JH, Bleackley J, Vermeulen L, Versteeg R, Koster J, et al. Mutations in the Ras-Raf Axis underlie the prognostic value of CD133 in colorectal cancer. Clin Cancer Res. 2012; 18:3132-41.
71. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436:720-4.
72. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008; 132:363-74.
73. Scurr LL, Pupo GM, Becker TM, Lai K, Schrama D, Haferkamp S, Irvine M, Scolyer RA, Mann GJ, Becker JC, et al. IGFBP7 is not required for B-RAF-induced melanocyte senescence. Cell. 2010; 141:717-27.
74. Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue L, Pritchard C, Marais R. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009; 15:294-303.
75. Rad R, Cadiñanos J, Rad L, Varela I, Strong A, Kriegl L, Constantino-Casas F, Eser S, Hieber M, Seidler B, et al. A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell. 2013; 24:15-29.
76. Carragher LA, Snell KR, Giblett SM, Aldridge VS, Patel B, Cook SJ, Winton DJ, Marais R, Pritchard CA. V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol Med. 2010; 2:458-71.
77. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359:1757-65.
78. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26:1626-34.
79. Rosty C, Young JP, Walsh MD, Clendenning M, Walters RJ, Pearson S, et al. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol. 2013; 26:825-34.
80. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, et al. 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. 2010; 28:466-74.
81. Imamura Y, Morikawa T, Liao X, Lochhead P, Kuchiba A, Yamauchi M, Qian ZR, Nishihara R, Meyerhardt JA, Haigis KM. Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res. 2012; 18:4753-63.
82. De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010; 304:1812-20.
83. Abubaker J, Bavi P, Al-Haqawi W, Sultana M, Al-Harbi S, Al-Sanea N, Abduljabbar A, Ashari LH, Alhomoud S, Al-Dayel F. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol. 2009; 219:435-45.
84. Brink M, de Goeij AF, Weijenberg MP, Roemen GM, Lentjes MH, Pachen MM. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis. 2003; 24:703-10.
85. Oliveira C, Velho S, Domingo E, Preto A, Hofstra RM, Hamelin R, Yamamoto H, Seruca R, Schwartz S Jr. Concomitant RASSF1A hypermethylation and KRAS/ BRAF mutations occur preferentially in MSI sporadic colorectal cancer. Oncogene. 2005; 24:7630-4.
86. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R. Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004; 116:855-67.
87. Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004; 6:313-9.
88. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009; 27: 2231-7.
89. Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAFand K-RAS-mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010; 127:367-80.
90. Fariña-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, van den Brule AJ. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 2010; 21: 2396-402.
91. Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B. BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer. 2006; 5:2.
92. Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' outcome. Br J Cancer. 2010; 102:1762-8.
93. Rampazzo E, Bertorelle R, Serra L, Terrin L, Candiotto C, Pucciarelli S, Del Bianco P, Nitti D, De Rossi A. Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers. Br J Cancer. 2010; 102:1300-5.
94. Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009; 101:465-72.
95. Yang S, Farray FA, Mack C, Posnik O, O'Brien MJ. BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol. 2004; 28:1452-9.
96. Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and metaanalysis. PLoS One. 2012; 7:e47054.
97. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993; 260:816-9.
98. Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Re. 1998; 58:1713-8.
99. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005; 23:609-18.
100. Koinuma K, Shitoh K, Miyakura Y, Furukawa T, Yamashita Y, Ota J, Ohki R, Choi YL, Wada T, Konishi F, et al. Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer. 2004; 108:237-42.
101. Sanchez JA, Krumroy L, Plummer S, Aung P, Merkulova A, Skacel M, DeJulius KL, Manilich E, Church JM, Casey G, Kalady MF. Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer. Br J Surg. 2009; 96:1196-204.
102. Wilson PM, Labonte MJ, Lenz HJ. Molecular markers in the treatment of metastatic colorectal cancer. Cancer J. 2010; 16:262-72.
103. Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espín E, Armengol M, et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet. 2004; 41:664-8.
104. Kriegl L, Jung A, Horst D, Rizzani A, Jackstadt R, Hermeking H, Gallmeier E, Gerbes AL, Kirchner T, Göke B, De Toni EN. Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer. PLoS One. 2012; 7:e51654.
105. Fujiwara T, Stolker JM, Watanabe T, Rashid A, Longo P, Eshleman JR, Booker S, Lynch HT, Jass JR, Green JS, et al. Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am J Pathol. 1998; 153: 1063-78.
106. Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology. 1996; 111:307-17.
107. Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev. 2004; 23:11-27.
108. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr D, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011; 29:1261-70.
109. Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM. Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol. 2005; 18:170-8.
110. Sawyer EJ, Cerar A, Hanby AM, Gorman P, Arends M, Talbot IC, Tomlinson IP. Molecular characteristics of serrated adenomas of the colorectum. Gut. 2002; 51:200-6.
111. Chan TL, Zhao W, Leung SY, Yuen ST. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003; 63:4878-81.
112. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004; 53:1137-44.
113. Jass JR, O'Brien J, Riddell RH, Snover DC. Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of surgically resected specimens of colorectal carcinoma: Association of Directors of Anatomic and Surgical Pathology. Am J Clin Pathol. 2008; 129:13-23.
114. O'Brien MJ. Hyperplastic and serrated polyps of the colorectum. Gastroenterol Clin North Am. 2007; 36: 947-68, viii.
115. O'Brien MJ, Yang S, Mack C, Xu H, Huang CS, Mulcahy E, Amorosino M, Farraye FA. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol. 2006; 30:1491-501.
116. Minoo P, Moyer MP, Jass JR. Role of BRAF-V600E in the serrated pathway of colorectal tumourigenesis. J Pathol. 2007; 212:124-33.
117. Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science. 1995; 270: 467-70.
118. DeRisi J, Penland L, Brown PO, Bittner ML, Meltzer PS, Ray M, Chen Y, Su YA, Trent JM. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet. 1996; 14:457-60.
119. Ramaswamy S, Golub TR. DNA microarrays in clinical oncology. J Clin Oncol. 2002; 20:1932-41.
120. Kitahara O, Katagiri T, Tsunoda T, Harima Y, Nakamura Y. Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis. Neoplasia. 2002; 4:295-303.
121. Mariadason JM, Arango D, Shi Q, Wilson AJ, Corner GA, Nicholas C, Aranes MJ, Lesser M, Schwartz EL, Augenlicht LH. Gene expression profiling-based prediction of response of colon carcinoma cells to 5-fluorouracil and camptothecin. Cancer Res. 2003; 63:8791-8812.
122. Dunican DS, McWilliam P, Tighe O, Parle-McDermott A, Croke DT. Gene expression differences between the microsatellite instability (MIN) and chromosomal instability (CIN) phenotypes in colorectal cancer revealed by high-density cDNA array hybridization. Oncogene. 2002; 21:3253-7.
123. Pavey S, Johansson P, Packer L, Taylor J, Stark M, Pollock PM, Walker GJ, Boyle GM, Harper U, Cozzi SJ, et al. Microarray expression profiling in melanoma reveals a BRAF mutation signature. Oncogene. 2004; 23:4060-7.
124. Joyce T, Oikonomou E, Kosmidou V, Makrodouli E, Bantounas I, Avlonitis S, Zografos G, Pintzas A. A molecular signature for oncogenic BRAF in human colon cancer cells is revealed by microarray analysis. Curr Cancer Drug Targets. 2012; 12:873-98.
125. Joyce T, Cantarella D, Isella C, Medico E, Pintzas A. A molecular signature for Epithelial to Mesenchymal transition in a human colon cancer cell system is revealed by large-scale microarray analysis. Clin Exp Metastasis. 2009; 26:569-87.
126. Tian S, Simon I, Moreno V, Roepman P, Tabernero J, Snel M, van't Veer L, Salazar R, Bernards R, Capella G. A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut. 2013; 62:540-9.
127. Popovici V, Budinska E, Tejpar S, Weinrich S, Estrella H, Hodgson G, Van Cutsem E, Xie T, Bosman FT, Roth AD, Delorenzi M. Identification of a poor-prognosis BRAFmutant-like population of patients with colon cancer. J Clin Oncol. 2012; 30:1288-95.
128. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, et al. 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. 2010; 11:753-62.
129. Cheng Y, Zhang G, Li G. Targeting MAPK pathway in melanoma therapy. Cancer Metastasis Rev. 2013; 32: 567-84.
130. Neuzillet C, Hammel P, Tijeras-Raballand A, Couvelard A, Raymond E. Targeting the Ras-ERK pathway in pancreatic adenocarcinoma. Cancer Metastasis Rev. 2013; 32:147-62.
131. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem. 1997; 272:14093-7.
132. Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai JK. Kand N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem. 1997; 272:14459-64.
133. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013; 503:548-51.
134. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat. Rev. Mol Cell Biol. 2004; 11:875-85.
135. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004; 64:7099-109.
136. Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, et al. Results of a phase III, randomized, placebocontrolled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009; 27:2823-30.
137. McDermott DF, Sosman JA, Gonzalez R, Hodi FS, Linette GP, Richards J, Jakub JW, Beeram M, Tarantolo S, Agarwala S, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol. 2008; 26:2178-85.
138. Takezawa K, Okamoto I, Yonesaka K, Hatashita E, Yamada Y, Fukuoka M, Nakagawa K. Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res. 2009; 69:6515-21.
139. Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, Halilovic E, Persaud Y, Xing F, Viale A, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010; 107:14903-8.
140. Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo JF, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010; 70:5518-27.
141. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 2008; 105:3041-6.
142. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363:809-19.
143. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012; 379:1893-901.
144. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011; 104:392-8.
145. http://clinicaltrials.gov/ct2/show/NCT00880321.
146. S. Bristol-Myers: clinicaltrials.gov: National Library of Medicine (U.S.) 2000-11/2012.
147. Mordant P, Loriot Y, Leteur C, Calderaro J, Bourhis J, Wislez M, Soria JC, Deutsch E. Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination. Mol Cancer Ther. 2010; 9:358-68.
148. Infante J, Falchook G, Lawrence D, Weber J, Kefford R, Bendell J, Kurzrock R, Shapiro G, Kudchadkar RR, Long GV, et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol. 2011; 29suppl; abstr CRA8503.
149. Gonzalez R, Ribas A, Daud A, Pavlick A, Gajewski T, Puzanov I, et al. Phase Ib study of vemurafenib in combination with the MEK inhibitor, GDC-0973, in patients (pts) with unresectable or metastatic BRAFV600 mutated melanoma (BRIM7). Ann Oncol. 2012; 23 doi:abstract LBA28_PR, ixe 19.10.1093/annonc/mds499.
150. Kefford R, Miller W, Tan D, Sullivan R, Long G, Dienstmann R, et al. Preliminary results from a phase Ib/ II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors. J Clin Oncol. 2013; 31: abstract 9029].
151. Novartis Pharmaceuticals: clinicaltrials.gov: National Library of Medicine 2(U.S.) 2000-11/2012.
152. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008; 68:4853-61.
153. Menzies AM, Long GV, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Deve Ther. 2012; 6:391-405.
154. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367: 1694-703.
155. Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi K, Kawakami T, et al. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res. 2003; 63:8132-7.
156. Singhal R, Kandel ES. The response to PAK1 inhibitor IPA3 distinguishes between cancer cells with mutations in BRAF and Ras Oncotarget. 2012; 3:700-708.
157. Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi K, Kawakami T, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006; 439:358-62.
158. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005; 2:e17.
159. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012; 486:537-40.
160. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012; 18:221-3.
161. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008; 359:366-77.
162. Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010117:77-88.
163. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012; 486:532-6.
164. Raponi M, Winkler H, Dracopoli NC. KRAS mutations predict response to EGFR inhibitors. Curr Opin Pharmacol. 2008; 8:413-8.
165. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009; 27:672-80.
166. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A. Oncogenic activation of the RAS/RAF signalling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007; 67:2643-8.
167. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 27:663-71.
168. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009; 360:563-72.
169. Modest DP, Reinacher-Schick A, Stintzing S, Giessen C, Tannapfel A, Laubender RP. Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis. Anticancer Drugs. 2012; 23:666-73.
170. Bokemeyer C, Kuczyk MA, Sehrt J. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med. 1994; 330:865.
171. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010; 468:973-7.
172. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011; 29:3085-96.
173. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3:75ra26.
174. Ogino SI, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, Giovannucci EL, Fuchs CS. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009; 58:90-6.
175. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008; 26:5705-12.
176. Mao C, Liao RY, Qiu LX, Wang XW, Ding H, Chen Q. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol. Rep. 2011; 38:2219-23.
177. Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, Besmer P, Antonescu CR. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008; 47:853-9.
178. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008; 105:3041-6.
179. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010; 467:596-9.
180. Cichowski K, Jänne PA. Drug discovery: inhibitors that activate. Nature. 2010; 464:358-9.
181. Chudnovsky Y, Adams AE, Robbins PB, Lin Q, Khavari PA. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Nat Genet. 2005; 37:745-9.
182. Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene. 2011; 30:366-71.
183. Vultur A, Villanueva J, Herlyn M. Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res. 2011; 17:1658-63.
184. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011; 480:387-90.
185. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012; 483:100-3.
186. Oikonomou E, Koc M, Sourkova V, Andera L, Pintzas A. Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance. PLoS One. 2011; 6:e21632.
187. Lemech C, Infante J, Arkenau HT. The potential for BRAF V600 inhibitors in advanced cutaneous melanoma: rationale and latest evidence. Ther Adv Med Oncol. 2012; 4:61-73.
188. Nakayama N, Nakayama K, Yeasmin S, Ishibashi M, Katagiri A, Iida K, Fukumoto M, Miyazaki K. KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer. Br J Cancer. 2008; 99:2020-8.
189. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88:593-602.
190. Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998; 12:2997-3007.
191. Blagosklonny MV. Prevention of cancer by inhibiting aging. Cancer Biol Ther. 2008; 7:1520-4.
192. Blagosklonny MV. Selective anti-cancer agents as antiaging drugs. Cancer Biol Ther. 2013; 14:1092-7.
193. Blagosklonny MV. Common drugs and treatments for cancer and age-related diseases: revitalizing answers to NCI's provocative questions. Oncotarget. 2012; 3:1711-24.
194. Leontieva OV, Demidenko ZN, Blagosklonny MV. MEK drives cyclin D1 hyperelevation during geroconversion. Cell Death Differ. 2013; 20:1241-9.
195. Vogelstein B, Kinzler KW. Digital PCR. Proc Natl Acad Sci U S A. 1999; 9:9236-41.
196. Prix L, Uciechowski P, Bockmann B, Giesing M, Schuetz AJ. Diagnostic biochip array for fast and sensitive detection of K-ras mutations in stool. Clin Chem. 2002; 48:428-35.
197. Fakhrai-Rad H, Pourmand N, Ronaghi M. Pyrosequencing: an accurate detection platform for single nucleotide polymorphisms. Hum Mutat. 2002; 19:479-85.
198. Kosmidou V, Oikonomou E, Vlassi M, Avlonitis S, Katseli A, Tsipras I, Mourtzoukou D, Kontogeorgos G, Zografos G, Pintzas A. Tumor Heterogeneity Revealed by KRAS, BRAF, and PIK3CA Pyrosequencing: KRAS and PIK3CA Intratumor Mutation Profile Differences and Their Therapeutic Implications. Hum Mutat. 2014; 35:329-40.
199. Milbury CA, Li J, Makrigiorgos GM. COLD-PCRenhanced high-resolution melting enables rapid, selective identification of low-level unknown mutations. Clin Chem. 2009; 55:2130-43.
200. Pao W, Kris MG, Iafrate AJ, Ladanyi M, Jänne PA, Wistuba II, Miake-Lye R, Herbst RS, Carbone DP, Johnson BE, et al. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res. 2009; 15:5317-22.
201. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011; 12:175-80.
202. Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue L, Pritchard C, Marais R. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009; 15:294-303.
203. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, et al. 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. 2010; 28:466-74.
204. Yuan ZX, Wang XY, Qin QY, Chen DF, Zhong QH, Wang L, Wang JP. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis. PLoS One. 2013; 8:e65995.
205. Ekedahl H, Cirenajwis H, Harbst K, Carneiro A, Nielsen K, Olsson H, Lundgren L, Ingvar C, Jönsson G. The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. Br J Dermatol. 2013; 169:1049-55.
206. Jakob JA, Bassett RL Jr, Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012; 118:4014-23.
207. Ohba T, Toyokawa G, Kometani T, Nosaki K, Hirai F, Yamaguchi M, Hamatake M, Seto T, Ichinose Y, Sugio K. The mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance. Surg Today. 2014; 44:478-86.
208. Guerra A, Fugazzola L, Marotta V, Cirillo M, Rossi S, Cirello V, Forno I, Moccia T, Budillon A, Vitale M. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab. 2012; 97:2333-40.
209. Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJ, Kornev AP, Taylor SS, Shaw AS. Allosteric activation of functionally asymmetric RAF kinase dimers. Cell. 2013; 154:1036-46.