Targeting Colon Cancers with Mutated BRAF and Microsatellite Instability

  • Paulo Matos
  • Peter JordanEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1110)


The subgroup of colon cancer (CRC) characterized by mutation in the BRAF gene and high mutation rate in the genomic DNA sequence, known as the microsatellite instability (MSI) phenotype, accounts for roughly 10% of the patients and derives from polyps with a serrated morphology. In this review, both features are discussed with regard to therapeutic opportunities. The most prevalent cancer-associated BRAF mutation is BRAF V600E that causes constitutive activation of the pro-proliferative MAPK pathway. Unfortunately, the available BRAF-specific inhibitors had little clinical benefit for metastatic CRC patients due to adaptive MAPK reactivation. Recent contributions for the development of new combination therapy approaches to pathway inhibition will be highlighted. In addition, we review the promising role of the recently developed immune checkpoint therapy for the treatment of this CRC subtype. The MSI phenotype of this subgroup results from an inactivated DNA mismatch repair system and leads to frameshift mutations with translation of new amino acid stretches and the generation of neo-antigens. This most likely explains the observed high degree of infiltration by tumour-associated lymphocytes. As cytotoxic lymphocytes are already part of the tumour environment, their activation by immune checkpoint therapy approaches is highly promising.


Alternative splicing BRAF Microsatellite instability RAC1b Serrated polyp pathway 



Work in the authors’ laboratory was supported by Fundação para a Ciência e Tecnologia (FCT) [through centre grant UID/MULTI/04046/2013 to BioISI, contract ‘FCT Investigator’ to PM, and fellowship SFRH/BPD/63395/2009 to VG] and by the Portuguese association Maratona da Saúde – Cancro 2014 to PJ.


  1. André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou J-F, de Gramont A (2015) Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol 33:4176–4187. CrossRefPubMedGoogle Scholar
  2. Atreya CE, Greene C, McWhirter RM, Ikram NS, Allen IE, Van Loon K, Venook AP, Yeh BM, Behr SC (2016) Differential radiographic appearance of BRAF V600E-mutant metastatic colorectal cancer in patients matched by primary tumor location. J Natl Compr Cancer Netw 14:1536–1543. CrossRefGoogle Scholar
  3. Bahrami A, Hesari A, Khazaei M, Hassanian SM, Ferns GA, Avan A (2018) The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer. J Cell Physiol 233:2162–2169. CrossRefPubMedGoogle Scholar
  4. Barras D, Missiaglia E, Wirapati P, Sieber OM, Jorissen RN, Love C, Molloy PL, Jones IT, McLaughlin S, Gibbs P, Guinney J, Simon IM, Roth AD, Bosman FT, Tejpar S, Delorenzi M (2017) BRAF V600E mutant colorectal cancer subtypes based on gene expression. Clin Cancer Res 23:104–115. CrossRefPubMedGoogle Scholar
  5. Bettington M, Walker N, Clouston A, Brown I, Leggett B, Whitehall V (2013) The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology 62:367–386. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bläker H, Alwers E, Arnold A, Herpel E, Tagscherer KE, Roth W, Jansen L, Walter V, Kloor M, Chang-Claude J, Brenner H, Hoffmeister M (2018) The association between mutations in BRAF and colorectal cancer-specific survival depends on microsatellite status and tumor stage. Clin Gastroenterol Hepatol.
  7. Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383:1490–1502. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bultman SJ (2017) Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol Nutr Food Res 61:1500902. CrossRefGoogle Scholar
  9. Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337. CrossRefGoogle Scholar
  10. Carethers JM (2017) Microsatellite instability pathway and EMAST in colorectal cancer. Curr Colorectal Cancer Rep 13:73–80. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Carethers J, Koi M, Tseng-Rogenski S (2015) EMAST is a form of microsatellite instability that is initiated by inflammation and modulates colorectal Cancer progression. Genes 6:185–205. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chen G, Gao C, Gao X, Zhang DH, Kuan S-F, Burns TF, Hu J (2018) Wnt/β-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer. Mol Cancer Ther 17:806–813. CrossRefPubMedGoogle Scholar
  13. Coffee EM, Faber AC, Roper J, Sinnamon MJ, Goel G, Keung L, Wang WV, Vecchione L, de Vriendt V, Weinstein BJ, Bronson RT, Tejpar S, Xavier RJ, Engelman JA, Martin ES, Hung KE (2013) Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res 19:2688–2698. CrossRefPubMedGoogle Scholar
  14. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA (2010) BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal 3:ra84. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della Pelle P, Dias-Santagata D, Hung KE, Flaherty KT, Piris A, Wargo JA, Settleman J, Mino-Kenudson M, Engelman JA (2012) EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2:227–235. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S (2015) Combined BRAF and MEK inhibition with Dabrafenib and Trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol 33:4023–4031. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Corcoran RB, André T, Atreya CE, Schellens JHM, Yoshino T, Bendell JC, Hollebecque A, McRee AJ, Siena S, Middleton G, Muro K, Gordon MS, Tabernero J, Yaeger R, O’Dwyer PJ, Humblet Y, De Vos F, Jung AS, Brase JC, Jaeger S, Bettinger S, Mookerjee B, Rangwala F, Van Cutsem E (2018) Combined BRAF, EGFR, and MEK inhibition in patients withBRAFV600E-mutant colorectal cancer. Cancer Discov 8:428–443. CrossRefPubMedGoogle Scholar
  18. Cortes-Ciriano I, Lee S, Park W-Y, Kim T-M, Park PJ (2017) A molecular portrait of microsatellite instability across multiple cancers. Nat Commun 8:15180. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Cosgarea I, Ritter C, Becker JC, Schadendorf D, Ugurel S (2017) Update on the clinical use of kinase inhibitors in melanoma. J Dtsch Dermatol Ges 15:887–893. CrossRefPubMedGoogle Scholar
  20. Crider KS, Yang TP, Berry RJ, Bailey LB (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for Folate’s role. Adv Nutr 3:21–38. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, Thibodeau SN (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:3455–3460PubMedGoogle Scholar
  22. Curtin K, Slattery ML, Samowitz WS (2011) CpG Island methylation in colorectal cancer: past, present and future. Pathol Res Int 2011:1–8. CrossRefGoogle Scholar
  23. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954. CrossRefPubMedGoogle Scholar
  24. Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290. CrossRefPubMedGoogle Scholar
  25. Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, Vecchiato N, Macrì E, Fornasarig M, Boiocchi M (1999) High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 154:1805–1813. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Duval A, Hamelin R (2002) Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res 62:2447–2454PubMedGoogle Scholar
  27. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A 106:20411–20416. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Fang M, Ou J, Hutchinson L, Green MR (2014) The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island methylator phenotype. Mol Cell 55:904–915. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol Mech Dis 6:479–507. CrossRefGoogle Scholar
  30. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Galon J (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964. CrossRefGoogle Scholar
  32. Gavin PG, Colangelo LH, Fumagalli D, Tanaka N, Remillard MY, Yothers G, Kim C, Taniyama Y, Kim SI, Choi HJ, Blackmon NL, Lipchik C, Petrelli NJ, O’Connell MJ, Wolmark N, Paik S, Pogue-Geile KL (2012) Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin Cancer Res 18:6531–6541. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Germano G, Lamba S, Rospo G, Barault L, Magrì A, Maione F, Russo M, Crisafulli G, Bartolini A, Lerda G, Siravegna G, Mussolin B, Frapolli R, Montone M, Morano F, de Braud F, Amirouchene-Angelozzi N, Marsoni S, D’Incalci M, Orlandi A, Giraudo E, Sartore-Bianchi A, Siena S, Pietrantonio F, Di Nicolantonio F, Bardelli A (2017) Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552:116–120. CrossRefPubMedGoogle Scholar
  34. Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R (2013) Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov 3:158–167. CrossRefPubMedGoogle Scholar
  35. Goulielmaki M, Koustas E, Moysidou E, Vlassi M, Sasazuki T, Shirasawa S, Zografos G, Oikonomou E, Pintzas A (2016) BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells. Oncotarget 7:9188–9221. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, Neumann A, Brattain MG, Chang J, Kim SJ, Kinzler KW, Vogelstein B, Willson JK, Markowitz S (1999) Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59:320–324PubMedGoogle Scholar
  37. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, Bot BM, Morris JS, Simon IM, Gerster S, Fessler E, De Sousa E, Melo F, Missiaglia E, Ramay H, Barras D, Homicsko K, Maru D, Manyam GC, Broom B, Boige V, Perez-Villamil B, Laderas T, Salazar R, Gray JW, Hanahan D, Tabernero J, Bernards R, Friend SH, Laurent-Puig P, Medema JP, Sadanandam A, Wessels L, Delorenzi M, Kopetz S, Vermeulen L, Tejpar S (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21:1350–1356. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hahn AW, Gill DM, Pal SK, Agarwal N (2017) The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. Immunotherapy 9:681–692. CrossRefPubMedGoogle Scholar
  39. Haugen AC, Goel A, Yamada K, Marra G, Nguyen T-P, Nagasaka T, Kanazawa S, Koike J, Kikuchi Y, Zhong X, Arita M, Shibuya K, Oshimura M, Hemmi H, Boland CR, Koi M (2008) Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Res 68:8465–8472. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Henriques A, Barros P, Moyer MP, Matos P, Jordan P (2015) Expression of tumour-related Rac1b antagonizes B-Raf-induced senescence in colorectal cells. Cancer Lett 369:368–375. CrossRefPubMedGoogle Scholar
  41. Hinoue T, Weisenberger DJ, Lange CPE, Shen H, Byun H-M, Van Den Berg D, Malik S, Pan F, Noushmehr H, van Dijk CM, Tollenaar RAEM, Laird PW (2012) Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 22:271–282. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Jia M, Gao X, Zhang Y, Hoffmeister M, Brenner H (2016) Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review. Clin Epigenetics 8:25. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Johnson IT, Belshaw NJ (2014) The effect of diet on the intestinal epigenome. Epigenomics 6:239–251. CrossRefPubMedGoogle Scholar
  46. Kai M, Yamamoto E, Sato A, Yamano H-O, Niinuma T, Kitajima H, Harada T, Aoki H, Maruyama R, Toyota M, Hatahira T, Nakase H, Sugai T, Yamashita T, Toyota M, Suzuki H (2017) Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer. Mol Carcinog 56:1743–1752. CrossRefPubMedGoogle Scholar
  47. Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C (2015) SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 34:5699–5708. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Koi M, Tseng-Rogenski SS, Carethers JM (2018) Inflammation-associated microsatellite alterations: mechanisms and significance in the prognosis of patients with colorectal cancer. World J Gastrointest Oncol 10:1–14. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa J-PJ, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L (2015) Phase II pilot study of Vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol 33:4032–4038. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Kumar S (2009) Combination of microsatellite instability and lymphocytic infiltrate as a prognostic Indicator for adjuvant therapy in colon cancer. Arch Surg 144:835. CrossRefPubMedGoogle Scholar
  51. Lavoie H, Therrien M (2015) Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 16:281–298. CrossRefPubMedGoogle Scholar
  52. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. CrossRefGoogle Scholar
  53. Levy A, Massard C, Soria J-C, Deutsch E (2016) Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: single centre subset analysis from a phase 1/2 trial. Eur J Cancer 68:156–162. CrossRefPubMedGoogle Scholar
  54. Li F, Mao G, Tong D, Huang J, Gu L, Yang W, Li G-M (2013) The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153:590–600. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43–51. CrossRefPubMedGoogle Scholar
  56. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, Demarini DJ, Irani JG, Casey M, Ouellet D, Martin A-M, Le N, Patel K, Flaherty K (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877–1888. CrossRefPubMedGoogle Scholar
  57. Mäkinen MJ (2007) Colorectal serrated adenocarcinoma. Histopathology 50:131–150. CrossRefPubMedGoogle Scholar
  58. Mao M, Tian F, Mariadason JM, Tsao CC, Lemos R, Dayyani F, Gopal YNV, Jiang Z-Q, Wistuba II, Tang XM, Bornman WG, Bollag G, Mills GB, Powis G, Desai J, Gallick GE, Davies MA, Kopetz S (2013) Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res 19:657–667. CrossRefPubMedGoogle Scholar
  59. Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, Kolch W (2011) Raf family kinases: old dogs have learned new tricks. Genes Cancer 2:232–260. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Matos P, Jordan P (2005) Expression of Rac1b stimulates NF-kappa B-mediated cell survival and G1/S progression. Exp Cell Res 305:292–299. CrossRefPubMedGoogle Scholar
  61. Matos P, Jordan P (2008) Increased Rac1b expression sustains colorectal tumor cell survival. Mol Cancer Res 6:1178–1184. CrossRefPubMedGoogle Scholar
  62. Matos P, Jordan P (2015) Beyond COX-inhibition: “side-effects” of ibuprofen on neoplastic development and progression. Curr Pharm Des 21:2978–2982. CrossRefPubMedGoogle Scholar
  63. Matos P, Collard JG, Jordan P (2003) Tumor-related alternatively spliced Rac1b is not regulated by Rho-GDP dissociation inhibitors and exhibits selective downstream signaling. J Biol Chem 278:50442–50448. CrossRefPubMedGoogle Scholar
  64. Matos P, Oliveira C, Velho S, Gonçalves V, da Costa LT, Moyer MP, Seruca R, Jordan P (2008) B-Raf(V600E) cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival. Gastroenterology 135:899–906. CrossRefPubMedGoogle Scholar
  65. Matos P, Kotelevets L, Goncalves V, Henriques A, Zerbib P, Moyer MP, Chastre E, Jordan P (2013) Ibuprofen inhibits colitis-induced overexpression of tumor-related Rac1b. Neoplasia 15:102–111. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Matos P, Gonçalves V, Jordan P (2016) Targeting the serrated pathway of colorectal cancer with mutation in BRAF. Biochim Biophys Acta BBA Rev Cancer 1866:51–63. CrossRefGoogle Scholar
  67. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee M-K, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Noffsinger AE (2009) Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol 4:343–364. CrossRefPubMedGoogle Scholar
  69. Ogino S, Nosho K, Irahara N, Meyerhardt JA, Baba Y, Shima K, Glickman JN, Ferrone CR, Mino-Kenudson M, Tanaka N, Dranoff G, Giovannucci EL, Fuchs CS (2009) Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG Island methylator phenotype. Clin Cancer Res 15:6412–6420. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Overman MJ, Lonardi S, Wong KYM, Lenz H-J, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine J-M, Cao ZA, Kamble S, Kopetz S, André T (2018) Durable clinical benefit with Nivolumab plus Ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer. J Clin Oncol 36:773–779. CrossRefPubMedGoogle Scholar
  71. Passardi A, Canale M, Valgiusti M, Ulivi P (2017) Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci 18:1324. CrossRefPubMedCentralGoogle Scholar
  72. Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S (2004) Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 91:469–475. CrossRefPubMedGoogle Scholar
  73. Pietrantonio F, Oddo D, Gloghini A, Valtorta E, Berenato R, Barault L, Caporale M, Busico A, Morano F, Gualeni AV, Alessi A, Siravegna G, Perrone F, Di Bartolomeo M, Bardelli A, de Braud F, Di Nicolantonio F (2016) MET-driven resistance to dual EGFR and BRAF blockade may be overcome by switching from EGFR to MET inhibition in BRAF-mutated colorectal cancer. Cancer Discov 6:963–971. CrossRefPubMedGoogle Scholar
  74. Pino MS, Kikuchi H, Zeng M, Herraiz M, Sperduti I, Berger D, Park D, Iafrate AJ, Zukerberg LR, Chung DC (2010) Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 138:1406–1417. CrossRefPubMedGoogle Scholar
  75. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427–430. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483:100–103. CrossRefPubMedGoogle Scholar
  78. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Rosenbaum MW, Bledsoe JR, Morales-Oyarvide V, Huynh TG, Mino-Kenudson M (2016) PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod Pathol 29:1104–1112. CrossRefPubMedGoogle Scholar
  80. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, Aranda E, Nordlinger B, Cisar L, Labianca R, Cunningham D, Van Cutsem E, Bosman F (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 28:466–474. CrossRefPubMedGoogle Scholar
  81. Sabbatino F, Wang Y, Wang X, Flaherty KT, Yu L, Pepin D, Scognamiglio G, Pepe S, Kirkwood JM, Cooper ZA, Frederick DT, Wargo JA, Ferrone S, Ferrone CR (2014) PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget 5:1926–1941. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, Slattery ML (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomark Prev 10:917–923Google Scholar
  83. Sapienza C, Issa J-P (2016) Diet, nutrition, and cancer epigenetics. Annu Rev Nutr 36:665–681. CrossRefPubMedGoogle Scholar
  84. Sarshekeh AM, Overman MJ, Kopetz S (2018) Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Future Oncol 14(18):1869–1874. CrossRefGoogle Scholar
  85. Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel DM (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134:988–997. CrossRefPubMedGoogle Scholar
  86. Seligmann JF, Fisher D, Smith CG, Richman SD, Elliott F, Brown S, Adams R, Maughan T, Quirke P, Cheadle J, Seymour M, Middleton G (2017) Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. Ann Oncol 28:562–568. CrossRefPubMedGoogle Scholar
  87. Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, Hernandez NS, Chen X, Ahmed S, Konishi K, Hamilton SR, Issa J-PJ (2007) Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A 104:18654–18659. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB, Kelley MC, Kefford RF, Chmielowski B, Glaspy JA, Sosman JA, van Baren N, Long GV, Ribas A, Lo RS (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80–93. CrossRefPubMedGoogle Scholar
  89. Shia J, Ellis NA, Paty PB, Nash GM, Qin J, Offit K, Zhang X-M, Markowitz AJ, Nafa K, Guillem JG, Wong WD, Gerald WL, Klimstra DS (2003) Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer. Am J Surg Pathol 27:1407–1417CrossRefGoogle Scholar
  90. Smyrk TC, Watson P, Kaul K, Lynch HT (2001) Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 91:2417–2422.<2417::AID-CNCR1276>3.0.CO;2-U CrossRefPubMedGoogle Scholar
  91. Snover DC (2011) Update on the serrated pathway to colorectal carcinoma. Hum Pathol 42:1–10. CrossRefPubMedGoogle Scholar
  92. Syn NL, Teng MWL, Mok TSK, Soo RA (2017) De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol 18:e731–e741. CrossRefPubMedGoogle Scholar
  93. Taieb J, Zaanan A, Le Malicot K, Julié C, Blons H, Mineur L, Bennouna J, Tabernero J, Mini E, Folprecht G, Van Laethem JL, Lepage C, Emile J-F, Laurent-Puig P (2016) Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 trial. JAMA Oncol 14:1–11. CrossRefGoogle Scholar
  94. Tajima A, Hess MT, Cabrera BL, Kolodner RD, Carethers JM (2004) The mismatch repair complex hMutS alpha recognizes 5-fluorouracil-modified DNA: implications for chemosensitivity and resistance. Gastroenterology 127:1678–1684CrossRefGoogle Scholar
  95. Tapia Rico G, Price TJ (2018) Atezolizumab for the treatment of colorectal cancer: the latest evidence and clinical potential. Expert Opin Biol Ther 18:449–457. CrossRefPubMedGoogle Scholar
  96. Toh JWT, de Souza P, Lim SH, Singh P, Chua W, Ng W, Spring KJ (2016) The potential value of immunotherapy in colorectal cancers: review of the evidence for programmed Death-1 inhibitor therapy. Clin Colorectal Cancer 15:285–291. CrossRefPubMedGoogle Scholar
  97. Tolcher AW, Peng W, Calvo E (2018) Rational approaches for combination therapy strategies targeting the MAP kinase pathway in solid tumors. Mol Cancer Ther 17:3–16. CrossRefPubMedGoogle Scholar
  98. Tseng-Rogenski SS, Hamaya Y, Choi DY, Carethers JM (2015) Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology 148:579–589. CrossRefPubMedGoogle Scholar
  99. Tutuka CSA, Andrews MC, Mariadason JM, Ioannidis P, Hudson C, Cebon J, Behren A (2017) PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation. Mol Cancer 16:112. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HFA, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268CrossRefGoogle Scholar
  101. Vaiopoulos AG, Athanasoula KC, Papavassiliou AG (2014) Epigenetic modifications in colorectal cancer: molecular insights and therapeutic challenges. Biochim Biophys Acta Mol Basis Dis 1842:971–980. CrossRefGoogle Scholar
  102. Vakana E, Pratt S, Blosser W, Dowless M, Simpson N, Yuan X-J, Jaken S, Manro J, Stephens J, Zhang Y, Huber L, Peng S-B, Stancato LF (2017) LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget 8:9251–9266. CrossRefPubMedGoogle Scholar
  103. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, Dermatologic Cooperative Oncology Group of Germany (DeCOG) (2014) The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4:94–109. CrossRefPubMedGoogle Scholar
  104. Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 95:8698–8702CrossRefGoogle Scholar
  105. Venderbosch S, Nagtegaal ID, Maughan TS, Smith CG, Cheadle JP, Fisher D, Kaplan R, Quirke P, Seymour MT, Richman SD, Meijer GA, Ylstra B, Heideman DAM, de Haan AFJ, Punt CJA, Koopman M (2014) Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 20:5322–5330. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Villanueva J, Infante JR, Krepler C, Reyes-Uribe P, Samanta M, Chen H-Y, Li B, Swoboda RK, Wilson M, Vultur A, Fukunaba-Kalabis M, Wubbenhorst B, Chen TY, Liu Q, Sproesser K, Demarini DJ, Gilmer TM, Martin A-M, Marmorstein R, Schultz DC, Speicher DW, Karakousis GC, Xu W, Amaravadi RK, Xu X, Schuchter LM, Herlyn M, Nathanson KL (2013) Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep 4:1090–1099. CrossRefPubMedPubMedCentralGoogle Scholar
  107. Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cancer Genome Project (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867. CrossRefPubMedGoogle Scholar
  108. Wang P-F, Chen Y, Song S-Y, Wang T-J, Ji W-J, Li S-W, Liu N, Yan C-X (2017) Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol 8:730. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793. CrossRefPubMedGoogle Scholar
  110. Williams DS, Bird MJ, Jorissen RN, Yu YL, Walker F, Zhang HH, Nice EC, Burgess AW (2010) Nonsense mediated decay resistant mutations are a source of expressed mutant proteins in Colon Cancer cell lines with microsatellite instability. PLoS One 5:e16012. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Yaeger R, Cercek A, O’Reilly EM, Reidy DL, Kemeny N, Wolinsky T, Capanu M, Gollub MJ, Rosen N, Berger MF, Lacouture ME, Vakiani E, Saltz LB (2015) Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res 21:1313–1320. CrossRefPubMedPubMedCentralGoogle Scholar
  112. Yamamoto H, Imai K (2015) Microsatellite instability: an update. Arch Toxicol 89:899–921. CrossRefPubMedGoogle Scholar
  113. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, Tsang G, Marimuthu A, Cho H, Wu G, Wang W, Fong D, Nguyen H, Shi S, Womack P, Nespi M, Shellooe R, Carias H, Powell B, Light E, Sanftner L, Walters J, Tsai J, West BL, Visor G, Rezaei H, Lin PS, Nolop K, Ibrahim PN, Hirth P, Bollag G (2015) RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 526:583–586. CrossRefPubMedGoogle Scholar
  114. Zhang Z, He Y, Tu X, Huang S, Chen Z, Wang L, Song J (2017) Mapping of DNA hypermethylation and hypomethylation induced by folate deficiency in sporadic colorectal cancer and clinical implication analysis of hypermethylation pattern in CBS promoter. Clin Lab 63:733–748.
  115. Zhi J, Li Z, Lv J, Feng B, Yang D, Xue L, Zhao Z, Zhang Y, Wu J, Jv Y, Jia Y (2018) Effects of PHA-665752 and vemurafenib combination treatment on in vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations. Oncol Lett 15:3904–3910.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Chemistry and Biochemistry, Faculty of SciencesUniversity of LisbonLisbonPortugal
  2. 2.BioISI – Biosystems & Integrative Sciences Institute, Faculty of SciencesUniversity of LisbonLisbonPortugal
  3. 3.Department of Human GeneticsNational Health Institute ‘Dr. Ricardo Jorge’LisbonPortugal

Personalised recommendations