Similar but different: Distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance

Oncotarget

Volumn 6, Issue 25, 2015, Pages 20785-20800

  Morkel, Markus ^a   Riemer, Pamela ^a,b   Bläker, Hendrik ^a,b   Sers, Christine ^a,b  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

BRAF; Colorectal cancer; KRAS; Signaling; Therapy

Indexed keywords

ALPELISIB; APC PROTEIN; B RAF KINASE; BEVACIZUMAB; BINIMETINIB; CETUXIMAB; DABRAFENIB; DACOMITINIB; ENCORAFENIB; EPIDERMAL GROWTH FACTOR RECEPTOR; FLUOROURACIL; GANITUMAB; MITOGEN ACTIVATED PROTEIN KINASE; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; PANITUMUMAB; TRAMETINIB; VEMURAFENIB; BRAF PROTEIN, HUMAN; KRAS PROTEIN, HUMAN; PROTEIN P21;

ADENOMATOUS POLYP; ADVANCED CANCER; ALLELIC IMBALANCE; AMINO ACID SUBSTITUTION; APC GENE; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER RESISTANCE; CARCINOGENESIS; COLORECTAL CANCER; DAB2IP GENE; FBXW7 GENE; GENE; GENE MUTATION; HETEROZYGOSITY LOSS; HUMAN; INTESTINAL STEM CELL; INTESTINE EPITHELIUM CELL; MICROSATELLITE INSTABILITY; MOLECULARLY TARGETED THERAPY; NONHUMAN; ONCOGENE BRAF; ONCOGENE K RAS; ONCOGENE N RAS; OVERALL SURVIVAL; RECTUM ADENOMA; SIGNAL TRANSDUCTION; TUMOR GROWTH; WNT SIGNALING PATHWAY; ANIMAL; COLORECTAL TUMOR; CYTOLOGY; DISEASE COURSE; DNA MUTATIONAL ANALYSIS; DRUG RESISTANCE; GENE EXPRESSION REGULATION; METABOLISM; MISSENSE MUTATION; MOUSE; MUTATION; STEM CELL;

ANIMALS; COLORECTAL NEOPLASMS; DISEASE PROGRESSION; DNA MUTATIONAL ANALYSIS; DRUG RESISTANCE, NEOPLASM; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MAP KINASE SIGNALING SYSTEM; MICE; MUTATION; MUTATION, MISSENSE; PROTO-ONCOGENE PROTEINS B-RAF; PROTO-ONCOGENE PROTEINS P21(RAS); SIGNAL TRANSDUCTION; STEM CELLS;

EID: 84940728715     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.4750     Document Type: Article

References (148)

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-74.
2. Oikonomou E, Koustas E, Goulielmaki M, Pintzas A. BRAF vs RAS oncogenes: Are mutations of the same pathway equal? Differential signalling and therapeutic implications. Oncotarget. 2014; 5:11752-77.
3. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011; 11:761-74.
4. Röring M, Brummer T. Aberrant B-Raf Signaling in Human Cancer-10 Years from Bench to Bedside. Critical Reviews in Oncogenesis. 2012; 17:97-121.
5. Castellano E, Downward J. RAS Interaction with PI3K: More Than Just Another Effector Pathway. Genes Cancer. 2011; 2:261-74.
6. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987; 327:293-7.
7. Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 1987; 327:298-303.
8. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988; 319:525-32.
9. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2015; 43:D805-11.
10. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6:pl1.
11. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487:330-7.
12. Scheffzek K, Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. 1997; 277:333-8.
13. Scheidig AJ, Burmester C, Goody RS. The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins. Structure. 1999; 7:1311-24.
14. Buhrman G, Holzapfel G, Fetics S, Mattos C. Allosteric modulation of Ras positions Q61 for a direct role incatalysis. Proc Natl Acad Sci USA. 2010; 107:4931-6.
15. Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, et al. Kirsten ras mutations in patients with colorectal cancer: the "RASCAL II" study. Br J Cancer. 2001; 85:692-6.
16. Bazan V, Migliavacca M, Zanna I, Tubiolo C, Grassi N, Latteri MA, et al. Specific codon K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol. 2002; 13:1438-46.
17. Grabocka E, Pylayeva-Gupta Y, Jones MJK, Lubkov V, Yemanaberhan E, Taylor L, et al. Wild-type H-and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell. 2014; 25:243-56.
18. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417:949-54.
19. Wan P, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004; 116:855-67.
20. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010; 3:ra84.
21. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal. 2011; 4:ra17.
22. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002; 418:934.
23. Irahara N, Baba Y, Nosho K, Shima K, Yan L, Dias-Santagata D, et al. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol. 2010; 19:157-63.
24. Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol. 2012; 13:39-51.
25. Prior IA, Hancock JF. Ras trafficking, localization and compartmentalized signalling. Semin Cell Dev Biol. 2012; 23:145-53.
26. Terai K, Matsuda M. The amino-terminal B-Raf-specific region mediates calcium-dependent homo-and hetero-dimerization of Raf. EMBO J. 2006; 25:3556-64.
27. Ding J, Tchaicheeyan O, Ambrosio L. Drosophila Raf's N terminus contains a novel conserved region and can contribute to torso RTK signaling. Genetics. 2010; 184:717-29.
28. Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem. 2005; 280:16244-53.
29. Brummer T, Martin P, Herzog S, Misawa Y, Daly RJ, Reth M. Functional analysis of the regulatory requirements of B-Raf and the B-Raf(V600E) oncoprotein. Oncogene. 2006; 25:6262-76.
30. Marais R, Light Y, Paterson HF, Mason CS, Marshall CJ. Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem. 1997; 272:4378-83.
31. Weber CK, Slupsky JR, Kalmes HA, Rapp UR. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001; 61:3595-8.
32. Ahlquist T, Bottillo I, Danielsen SA, Meling GI, Rognum TO, Lind GE, et al. RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. Neoplasia. 2008; 10:680-686.
33. Stites EC, Trampont PC, Haney LB, Walk SF, Ravichandran KS. Cooperation between Noncanonical Ras Network Mutations. Cell Rep. 2015.
34. Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med. 2010; 286-94.
35. Zhang Z, Chen Y, Tang J, Xie X. Frequent loss expression of dab2 and promotor hypermethylation in human cancers: a meta-analysis and systematic review. Pak J Med Sci. 2014; 30:432-7.
36. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990; 61:759-67.
37. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011; 6:479-507.
38. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459:262-5.
39. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2010; 469:415.
40. Wong VWY, Stange DE, Page ME, Buczacki S, Wabik A, Itami S, et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat Cell Biol. 2012; 14:401-8.
41. Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol. 2013.
42. Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009; 457:608-11.
43. Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature. 2009; 457:603-7.
44. Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med. 2015; 256-62.
45. Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. 1993; 262:1734-7.
46. Farr CJ, Marshall CJ, Easty DJ, Wright NA, Powell SC, Paraskeva C. A study of ras gene mutations in colonic adenomas from familial polyposis coli patients. Oncogene. 1988; 3:673-8.
47. Sansom OJ, Meniel V, Wilkins JA, Cole AM, Oien KA, Marsh V, et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc Natl Acad Sci USA. 2006; 103:14122-7.
48. Janssen K-P, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P, et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006; 131:1096-109.
49. Phelps RA, Chidester S, Dehghanizadeh S, Phelps J, Sandoval IT, Rai K, et al. A Two-Step Model for Colon Adenoma Initiation and Progression Caused by APC Loss. Cell. 2009; 137:623-34.
50. Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010; pp. 2088-2100.
51. Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011; 42:1-10.
52. Bettington M, Walker N, Clouston A, Brown I, Leggett B, Whitehall V. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology. 2013; 62:367-86.
53. Rosenberg DW, Yang S, Pleau DC, Greenspan EJ, Stevens RG, Rajan TV, et al. Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res. 2007; 67:3551-4.
54. 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.
55. Burnett-Hartman AN, Newcomb PA, Potter JD, Passarelli MN, Phipps AI, Wurscher MA, et al. Genomic aberrations occurring in subsets of serrated colorectal lesions but not conventional adenomas. Cancer Res. 2013; 73:2863-72.
56. Bongers G, Muniz LR, Pacer ME, Iuga AC, Thirunarayanan N, Slinger E, et al. A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans. Gastroenterology. 2012; 143:730-40.
57. Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004; 5:375-87.
58. Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, 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.
59. Bennecke M, Kriegl L, Bajbouj M, Retzlaff K, Robine S, Jung A, et al. Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell. 2010 ed. 2010; 18:135-46.
60. Carragher LAS, Snell KR, Giblett SM, Aldridge VSS, Patel B, Cook SJ, et al. V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol Med. 2010; 2:458-71.
61. Rad R, Cadiñanos J, Rad L, Varela I, Strong A, Kriegl L, et al. A Genetic Progression Model of Braf(V600E)-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention. Cancer Cell. 2013; 24:15-29.
62. Yachida S, Mudali S, Martin SA, Montgomery EA, Iacobuzio-Donahue CA. Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol. 2009; 33:1823-32.
63. Wu JM, Montgomery EA, Iacobuzio-Donahue CA. Frequent beta-catenin nuclear labeling in sessile serrated polyps of the colorectum with neoplastic potential. Am J Clin Pathol. 2008; 129:416-23.
64. Krausova M, Korinek V. Wnt signaling in adult intestinal stem cells and cancer. Cell Signal. 2014; 26:570-9.
65. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007; 50:113-30.
66. Janssen K-P, Marjou El F, Pinto D, Sastre X, Rouillard D, Fouquet C, et al. Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice. Gastroenterology. 2002; 123:492-504.
67. Feng Y, Bommer GT, Zhao J, Green M, Sands E, Zhai Y, et al. Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology. 2011; 141:1003-1013.e1-10.
68. Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science. 2013; 342:995-8.
69. Snippert HJ, Schepers AG, van Es JH, Simons BD, Clevers H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 2014; 15:62-9.
70. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties. Cell. 2013; 152:25-38.
71. Riemer P, Sreekumar A, Reinke S, Rad R, Schäfer R, Sers C, et al. Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity. Oncogene. 2015; 34:3164-75.
72. Konishi K, Yamochi T, Makino R, Kaneko K, Yamamoto T, Nozawa H, et al. Molecular differences between sporadic serrated and conventional colorectal adenomas. Clin Cancer Res. 2004; 10:3082-90.
73. 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.
74. Oliveira C, Velho S, Moutinho C, Ferreira A, Preto A, Domingo E, et al. KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene. 2007; 26:158-63.
75. Phipps AI, Limburg PJ, Baron JA, Burnett-Hartman AN, Weisenberger DJ, Laird PW, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015; 148:77-87.e2.
76. Fang M, Ou J, Hutchinson L, Green MR. The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype. Mol Cell. 2014; 55:904-15.
77. Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012; 61:847-54.
78. Bae JM, Kim JH, Cho N-Y, Kim TY, Kang GH. Prognostic implication of the CpG island methylator phenotype in colorectal cancers depends on tumour location. Br J Cancer. 2013; 109:1004-12.
79. Kohonen-Corish MRJ, Tseung J, Chan C, Currey N, Dent OF, Clarke S, et al. KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer. Int J Cancer. 2014; 134:2820-8.
80. Minsky BD. Unique considerations in the patient with rectal cancer. Semin Oncol. 2011; 38:542-51.
81. Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA. 2007; 104:18654-9.
82. De Sousa E Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LPMH, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013; 19:614-8.
83. Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013; 19:619-25.
84. Rak J, Filmus J, Finkenzeller G, Grugel S, Marmé D, Kerbel RS. Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 1995; 14:263-77.
85. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005; 17:548-58.
86. Relógio A, Thomas P, Medina-Pérez P, Reischl S, Bervoets S, Gloc E, et al. Ras-mediated deregulation of the circadian clock in cancer. PLoS Genet. 2014; 10:e1004338.
87. Herr R, Köhler M, Andrlová H, Weinberg F, Möller Y, Halbach S, et al. B-Raf inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells. Cancer Res. 2015; 75:216-29.
88. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science. 1993; 260:85-8.
89. Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction-a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006; 3:448-57.
90. Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007; 21:3214-31.
91. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission Possible? Nat Rev Drug Discov. 2014; 13:828-51.
92. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359:1757-65.
93. Van Cutsem E, Köhne C-H, Hitre E, Zaluski J, Chang Chien C-R, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360:1408-17.
94. Douillard J-Y, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013; 369:1023-34.
95. Heinemann V, Douillard JY, Ducreux M, Peeters M. Targeted therapy in metastatic colorectal cancer-An example of personalised medicine in action. Cancer Treat Rev. 2013; 39:592-601.
96. Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis. Eur J Cancer. 2015; 51:587-94.
97. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012; 486:532-6.
98. Diaz LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012; 486:537-40.
99. Misale S, Arena S, Lamba S, Siravegna G, Lallo A, Hobor S, et al. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci Transl Med. 2014; 6:224ra26.
100. Bozic I, Allen B, Nowak MA. Dynamics of targeted cancer therapy. Trends Mol Med. 2012; 18:311-6.
101. Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, et al. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015; 47:209-16.
102. Robertson-Tessi M, Anderson ARA. Big Bang and context-driven collapse. Nat Genet. 2015; 47:196-7.
103. Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Lee RJ, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010; 28:.
104. Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, et al. 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. 2004; 22:4456-62.
105. Corbalan-Garcia S, Yang SS, Degenhardt KR, Bar-Sagi D. Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2. Mol Cell Biol. 1996; 16:5674-82.
106. Douville E, Downward J. EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2. Oncogene. 1997; 15:373-83.
107. Li X, Huang Y, Jiang J, Frank SJ. ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling. Cell Signal. 2008; 20:2145-55.
108. Hanafusa H, Torii S, Yasunaga T, Nishida E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol. 2002; 4:850-8.
109. Sun C, Hobor S, Bertotti A, Zecchin D, Huang S, Galimi F, et al. Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3. Cell Rep. 2014; 7:86-93.
110. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012; 483:100-3.
111. Klinger B, Sieber A, Fritsche-Guenther R, Witzel F, Berry L, Schumacher D, et al. Network quantification of EGFR signaling unveils potential for targeted combination therapy. Mol Syst Biol. 2013; 9:673.
112. Dougherty MK, Müller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005; 17:215-24.
113. Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F, et al. A module of negative feedback regulators defines growth factor signaling. Nat Genet. 2007; 39:503-12.
114. Fritsche-Guenther R, Witzel F, Sieber A, Herr R, Schmidt N, Braun S, et al. Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. Mol Syst Biol. 2011; 7:489.
115. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao Y-M, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 2009; 69:4286-93.
116. Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med. 2013; 19:1401-9.
117. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012; 2:227-35.
118. Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012; 72:779-89.
119. Capalbo C, Marchetti P, Coppa A, Calogero A, Anastasi E, Buffone A, et al. Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: a case report. Cancer Biol Ther. 2014; 15:826-31.
120. Yaeger R, Cercek A, O'Reilly EM, Reidy DL, Kemeny N, Wolinsky T, et al. Pilot Trial of Combined BRAF, and EGFR Inhibition in BRAF-Mutant Metastatic Colorectal Cancer Patients. Clin Cancer Res. 2015; 21:1313-20.
121. Corcoran RB, Atreya CE, Falchook GS, Infante JR, Hamid O, Messersmith WA, et al. Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): Updated efficacy and biomarker analysis. J Clin Oncol. 32:5s, 2014.
122. Bendell JC, Atreya CE, André T, Tabernero J, Gordon MS, Bernards R, et al. Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol. 32:5s, 2014.
123. Hong DS, Van Karlyle Morris, Fu S, Overman MJ, Piha-Paul SA, Kee BK, et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer. J Clin Oncol. 32:5s, 2014.
124. Tabernero J, Chan E, Baselga J, Blay J-Y, Chau I, Hyman DM, et al. VE-BASKET, a Simon 2-stage adaptive design, phase II, histology-independent study in nonmelanoma solid tumors harboring BRAF V600 mutations (V600m): Activity of vemurafenib (VEM) with or without cetuximab (CTX) in colorectal cancer (CRC). J Clin Oncol. 32:5s, 2014.
125. Ahronian LG, Sennott EM, Van Allen EM, Wagle N, Kwak EL, Faris JE, et al. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. Cancer Discov. 2015; 5:358-67.
126. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010; 464:427-30.
127. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF, and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010; 140:209-21.
128. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010; 464:431-5.
129. Cox AD, Der CJ. The RAF Inhibitor Paradox Revisited. Cancer Cell. 2012; 21:147-9.
130. Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS-versus BRAF-driven cancers. Nature. 2013; 501:232-6.
131. Condelli V, Piscazzi A, Sisinni L, Matassa DS, Maddalena F, Lettini G, et al. TRAP1 is involved in BRAF regulation and downstream attenuation of ERK phosphorylation and cell-cycle progression: a novel target for BRAF-mutated colorectal tumors. Cancer Res. 2014; 74:6693-704.
132. Parsons DW, Wang T-L, Samuels Y, Bardelli A, Cummins JM, DeLong L, et al. Colorectal cancer: mutations in a signalling pathway. Nature. 2005; 436:792.
133. She Q-B, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T, et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell. 2010; 18:39-51.
134. Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature. 2014; 513:105-9.
135. Van Geel R, Elez E, Bendell JC, Faris JE, Lolkema MPJK, Eskens F, et al. Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the a-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol. 32:5s, 2014. 32(5s, 2014).
136. Coffee EM, Faber AC, Roper J, Sinnamon MJ, Goel G, Keung L, et al. Concomitant BRAF, and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res. 2013; 19:2688-98.
137. Faller WJ, Jackson TJ, Knight JRP, Ridgway RA, Jamieson T, Karim SA, et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2015; 517:497-500.
138. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, et al: Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974Proc Natl Acad Sci USA. 2013;110: 20224-9.
139. Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al. The Hippo effector YAP promotes resistance to RAF-and MEK-targeted cancer therapies. Nat Genet. 2015; 47:250-6.
140. Keren-Paz A, Emmanuel R, Samuels Y. YAP and the drug resistance highway. Nat Genet. 2015; 47:193-4.
141. Schulze A, Lehmann K, Jefferies HB, McMahon M, Downward J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev. 2001; 15:981-94.
142. Kreeger PK, Mandhana R, Alford SK, Haigis KM, Lauffenburger DA. RAS mutations affect tumor necrosis factor-induced apoptosis in colon carcinoma cells via ERK-modulatory negative and positive feedback circuits along with non-ERK pathway effects. Cancer Res. 2009; 69:8191-9.
143. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012; 487:500-4.
144. Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015; 47:320-9.
145. Polyak K, Marusyk A. Cancer: Clonal cooperation. Nature. 2014; 508:52-3.
146. Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med. 2015; 7:29ra41.
147. Sers C, Kuner R, Falk CS, Lund P, Sueltmann H, Braun M, et al. Down-regulation of HLA Class, I, and NKG2D ligands through a concerted action of MAPK and DNA methyltransferases in colorectal cancer cells. Int J Cancer. 2009; 125:1626-39.
148. Koelzer VH, Dawson H, Andersson E, Karamitopoulou E, Masucci GV, Luigi A et al. Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome. Transl Res. 2015; pii:S1931-5244(15)00083-3.