Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies

Langenbeck's Archives of Surgery

Volumn 400, Issue 2, 2015, Pages 129-143

  Akkad, Jamil ^a   Bochum, Sylvia ^a   Martens, Uwe M ^a,b  

^a SLK Kliniken Heilbronn GmbH   (Germany)

^b UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Aflibercept; Bevacizumab; Biomarker; BRAF; Cancer stem cells; Cetuximab; Colorectal cancer; EGFR; Genomics; KRAS; NGS; Panitumumab; PD 1; PI3K; Precision medicine; RAS; Regorafenib; Targeted therapy; VEGF; WNT

Indexed keywords

AFATINIB; AFLIBERCEPT; B RAF KINASE; BEVACIZUMAB; BINIMETINIB; CETUXIMAB; COBIMETINIB; DALOTUZUMAB; DULIGOTUZUMAB; EPIDERMAL GROWTH FACTOR RECEPTOR; FLUOROURACIL; FOLINIC ACID; FUTUXIMAB; GEDATOLISIB; IRINOTECAN; K RAS PROTEIN; LAPATINIB; NERATINIB; PANITUMUMAB; PERTUZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; RAF PROTEIN; RAS PROTEIN; REGORAFENIB; TIVANTINIB; TRASTUZUMAB; TUMOR MARKER; UNINDEXED DRUG; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY;

ANGIOGENESIS; ARAF GENE; BRAF GENE; CANCER CLASSIFICATION; CANCER PROGNOSIS; CANCER RESISTANCE; CANCER STAGING; CANCER SURVIVAL; CHROMOSOMAL INSTABILITY; CIRCULATING TUMOR CELL; COLORECTAL CANCER; CPG ISLAND; CRAF GENE; DNA METHYLATION; DRUG TARGETING; EGFR GENE; ENZYME ACTIVITY; EPIGENETICS; GENE MUTATION; GENOMICS; HUMAN; MICROSATELLITE INSTABILITY; MOLECULARLY TARGETED THERAPY; ONCOGENE K RAS; ONCOGENE N RAS; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHENOTYPE; PRIORITY JOURNAL; PROTEOMICS; PTEN GENE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; SOMATIC HYPERMUTATION; TUMOR SUPPRESSOR GENE; WNT SIGNALING PATHWAY; COLORECTAL NEOPLASMS; DRUG EFFECTS; FEMALE; FORECASTING; GENE EXPRESSION REGULATION; GENETICS; INCIDENCE; MALE; METABOLISM; PROCEDURES; PROGNOSIS; STANDARDS; TREATMENT OUTCOME; TRENDS;

ANGIOGENESIS INHIBITORS; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; CLINICAL TRIALS, PHASE II AS TOPIC; COLORECTAL NEOPLASMS; FEMALE; FORECASTING; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; INCIDENCE; MALE; MOLECULAR TARGETED THERAPY; PRECISION MEDICINE; PROGNOSIS; PROTEOMICS; TREATMENT OUTCOME;

EID: 84925519646     PISSN: 14352443     EISSN: 14352451     Source Type: Journal    
DOI: 10.1007/s00423-015-1276-0     Document Type: Review

References (131)

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer J Int Cancer 136(5):E359–E386. doi:10.1002/ijc.29210
2. Gill S, Blackstock AW, Goldberg RM (2007) Colorectal cancer. Mayo Clin Proc 82(1):114–129. doi:10.4065/82.1.114
3. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (2010) Colorectal cancer. Lancet 375(9719):1030–1047. doi:10.1016/S0140-6736(10)60353-4
4. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Muller S, Link H, Niederle N, Rost A, Hoffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15(10):1065–1075. doi:10.1016/S1470-2045(14)70330-4
5. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 32(21):2240–2247. doi:10.1200/JCO.2013.53.2473
6. Ciardiello F, Arnold D, Casali PG, Cervantes A, Douillard J-Y, Eggermont A, Eniu A, McGregor K, Peters S, Piccart M, Popescu R, Van Cutsem E, Zielinski C, Stahel R (2014) Delivering precision medicine in oncology today and in future—the promise and challenges of personalised cancer medicine: a position paper by the European Society for Medical Oncology (ESMO). Ann Onc 25(9):1673–1678. doi:10.1093/annonc/mdu217
7. Diamandis M, White NM, Yousef GM (2010) Personalized medicine: marking a new epoch in cancer patient management. Mol Cancer Res MCR 8(9):1175–1187. doi:10.1158/1541-7786.MCR-10-0264
8. Wolpin BM, Mayer RJ (2008) Systemic treatment of colorectal cancer. Gastroenterology 134(5):1296–1310. doi:10.1053/j.gastro.2008.02.098
9. Kim TM, Lee SH, Chung YJ (2013) Clinical applications of next-generation sequencing in colorectal cancers. World J Gastroenterol WJG 19(40):6784–6793. doi:10.3748/wjg.v19.i40.6784
10. Cancer Genome Atlas N (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337. doi:10.1038/nature11252
11. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, Davies SR, Wang S, Wang P, Kinsinger CR, Rivers RC, Rodriguez H, Townsend RR, Ellis MJ, Carr SA, Tabb DL, Coffey RJ, Slebos RJ, Liebler DC, Nci C (2014) Proteogenomic characterization of human colon and rectal cancer. Nature 513(7518):382–387. doi:10.1038/nature13438
12. Dienstmann R, Salazar R, Tabernero J (2014) The evolution of our molecular understanding of colorectal cancer: what we are doing now, what the future holds, and how tumor profiling is just the beginning. In: 2014 ASCO EDUCATIONAL BOOK. pp 91–99
13. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767
14. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507. doi:10.1146/annurev-pathol-011110-130235
15. Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138(6):2073–2087.e2073. doi:10.1053/j.gastro.2009.12.064
16. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff 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 HF, 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(4):261–268
17. Murphy KM, Zhang S, Geiger T, Hafez MJ, Bacher J, Berg KD, Eshleman JR (2006) Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn JMD 8(3):305–311. doi:10.2353/jmoldx.2006.050092
18. Kim TM, Laird PW, Park PJ (2013) The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155(4):858–868. doi:10.1016/j.cell.2013.10.015
19. Peltomaki P (2005) Lynch syndrome genes. Fam Cancer 4(3):227–232. doi:10.1007/s10689-004-7993-0
20. Sinicrope FA, Sargent DJ (2012) Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res Off J Am Assoc Cancer Res 18(6):1506–1512. doi:10.1158/1078-0432.CCR-11-1469
21. Samowitz WS (2008) Genetic and epigenetic changes in colon cancer. Exp Mol Pathol 85(1):64–67. doi:10.1016/j.yexmp.2008.03.008
22. Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A, O’Connor T, Ward R (2002) CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122(5):1376–1387
23. Vilar E, Tabernero J (2013) Molecular dissection of microsatellite instable colorectal cancer. Cancer Discov 3(5):502–511. doi:10.1158/2159-8290.CD-12-0471
24. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466(7303):253–257. doi:10.1038/nature09165
25. Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G (2014) Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26(4):577–590. doi:10.1016/j.ccr.2014.07.028
26. Salazar R, Roepman P, Capella G, Moreno V, Simon I, Dreezen C, Lopez-Doriga A, Santos C, Marijnen C, Westerga J, Bruin S, Kerr D, Kuppen P, van de Velde C, Morreau H, Van Velthuysen L, Glas AM, Van’t Veer LJ, Tollenaar R (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 29(1):17–24. doi:10.1200/JCO.2010.30.1077
27. Wang Y, Jatkoe T, Zhang Y, Mutch MG, Talantov D, Jiang J, McLeod HL, Atkins D (2004) Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol Off J Am Soc Clin Oncol 22(9):1564–1571. doi:10.1200/JCO.2004.08.186
28. Eschrich S, Yang I, Bloom G, Kwong KY, Boulware D, Cantor A, Coppola D, Kruhoffer M, Aaltonen L, Orntoft TF, Quackenbush J, Yeatman TJ (2005) Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol Off J Am Soc Clin Oncol 23(15):3526–3535. doi:10.1200/JCO.2005.00.695
29. Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, Lannon WA, Grotzinger C, Del Rio M, Lhermitte B, Olshen AB, Wiedenmann B, Cantley LC, Gray JW, Hanahan D (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19(5):619–625. doi:10.1038/nm.3175
30. Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Flejou JF, Benchimol D, Berger A, Lagarde A, Pencreach E, Piard F, Elias D, Parc Y, Olschwang S, Milano G, Laurent-Puig P, Boige V (2013) Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 10(5):e1001453. doi:10.1371/journal.pmed.1001453
31. Budinska E, Popovici V, Tejpar S, D’Ario G, Lapique N, Sikora KO, Di Narzo AF, Yan P, Hodgson JG, Weinrich S, Bosman F, Roth A, Delorenzi M (2013) Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol 231(1):63–76. doi:10.1002/path.4212
32. Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, Snel MH, Chresta CM, Rosenberg R, Nitsche U, Macarulla T, Capella G, Salazar R, Orphanides G, Wessels LF, Bernards R, Simon IM (2014) Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer J Int Cancer 134(3):552–562. doi:10.1002/ijc.28387
33. 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(4):988–997. doi:10.1053/j.gastro.2008.01.015
34. 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(12):e16012. doi:10.1371/journal.pone.0016012
35. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X (2015) Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 21(1):24–33. doi:10.1016/j.molmed.2014.10.009
36. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol Off J Am Soc Clin Oncol 23(3):609–618. doi:10.1200/JCO.2005.01.086
37. 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(3):247–257. doi:10.1056/NEJMoa022289
38. Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz JF, Sinicrope F, Gallinger S (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol Off J Am Soc Clin Oncol 28(20):3219–3226. doi:10.1200/JCO.2009.27.1825
39. Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, Pinol V, Xicola RM, Bujanda L, Rene JM, Clofent J, Bessa X, Morillas JD, Nicolas-Perez D, Paya A, Alenda C, Gastrointestinal Oncology Group of the Spanish Gastroenterological A (2006) Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 55(6):848–855. doi:10.1136/gut.2005.073015
40. Zaanan A, Cuilliere-Dartigues P, Guilloux A, Parc Y, Louvet C, de Gramont A, Tiret E, Dumont S, Gayet B, Validire P, Flejou JF, Duval A, Praz F (2010) Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. AnnOncol Off J Eur Soc Med Oncol ESMO 21(4):772–780. doi:10.1093/annonc/mdp383
41. Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, Young JP, Barker MA, Jass JR, Hopper J, Gallinger S, Bapat B, Redston M, Thibodeau SN (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol Off J Am Soc Clin Oncol 20(4):1043–1048
42. Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3):282–303. doi:10.1016/j.ccr.2014.02.025
43. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358(11):1160–1174. doi:10.1056/NEJMra0707704
44. Fan Z, Lu Y, Wu X, Mendelsohn J (1994) Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. J Biol Chem 269(44):27595–27602
45. De Mattos-Arruda L, Dienstmann R, Tabernero J (2011) Development of molecular biomarkers in individualized treatment of colorectal cancer. Clin Colorectal Cancer 10(4):279–289. doi:10.1016/j.clcc.2011.03.030
46. Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Penault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 27(30):5068–5074. doi:10.1200/JCO.2008.21.3744
47. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA 3rd, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 25(22):3230–3237. doi:10.1200/JCO.2006.10.5437
48. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. doi:10.1038/35052073
49. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Janne PA (2011) Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 3(99):99ra86. doi:10.1126/scitranslmed.3002442
50. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Seshagiri S, Serrano S, Himmelbauer H, Bellmunt J, Rovira A, Settleman J, Bosch F, Albanell J (2012) Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 18(2):221–223. doi:10.1038/nm.2609
51. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 26(10):1626–1634. doi:10.1200/JCO.2007.14.7116
52. de Reynies A, Boige V, Milano G, Faivre J, Laurent-Puig P (2008) KRAS mutation signature in colorectal tumors significantly overlaps with the cetuximab response signature. J Clin Oncol Off J Am Soc Clin Oncol 26(13):2228–2230. doi:10.1200/JCO.2007.15.9186, author reply 2230–2221
53. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboue R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96(8):1166–1169. doi:10.1038/sj.bjc.6603685
54. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouche O, Landi B, Louvet C, Andre T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 26(3):374–379. doi:10.1200/JCO.2007.12.5906
55. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995. doi:10.1158/0008-5472.CAN-06-0191
56. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol Off J Am Soc Clin Oncol 28(31):4697–4705. doi:10.1200/JCO.2009.27.4860
57. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11(11):761–774. doi:10.1038/nrc3106
58. 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 Off J Am Soc Clin Oncol 28(3):466–474. doi:10.1200/JCO.2009.23.3452
59. Janakiraman M, Vakiani E, Zeng Z, Pratilas CA, Taylor BS, Chitale D, Halilovic E, Wilson M, Huberman K, Ricarte Filho JC, Persaud Y, Levine DA, Fagin JA, Jhanwar SC, Mariadason JM, Lash A, Ladanyi M, Saltz LB, Heguy A, Paty PB, Solit DB (2010) Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res 70(14):5901–5911. doi:10.1158/0008-5472.CAN-10-0192
60. Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10(12):842–857. doi:10.1038/nrc2960
61. Stephen AG, Esposito D, Bagni RK, McCormick F (2014) Dragging ras back in the ring. Cancer Cell 25(3):272–281. doi:10.1016/j.ccr.2014.02.017
62. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, Frohling S, Chan EM, Sos ML, Michel K, Mermel C, Silver SJ, Weir BA, Reiling JH, Sheng Q, Gupta PB, Wadlow RC, Le H, Hoersch S, Wittner BS, Ramaswamy S, Livingston DM, Sabatini DM, Meyerson M, Thomas RK, Lander ES, Mesirov JP, Root DE, Gilliland DG, Jacks T, Hahn WC (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108–112. doi:10.1038/nature08460
63. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23(1):121–128. doi:10.1016/j.ccr.2012.11.007
64. Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137(5):835–848. doi:10.1016/j.cell.2009.05.006
65. Grabocka E, Pylayeva-Gupta Y, Jones MJ, Lubkov V, Yemanaberhan E, Taylor L, Jeng HH, Bar-Sagi D (2014) Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 25(2):243–256. doi:10.1016/j.ccr.2014.01.005
66. Azoitei N, Hoffmann CM, Ellegast JM, Ball CR, Obermayer K, Gossele U, Koch B, Faber K, Genze F, Schrader M, Kestler HA, Dohner H, Chiosis G, Glimm H, Frohling S, Scholl C (2012) Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33. J Exp Med 209(4):697–711. doi:10.1084/jem.20111910
67. De Raedt T, Walton Z, Yecies JL, Li D, Chen Y, Malone CF, Maertens O, Jeong SM, Bronson RT, Lebleu V, Kalluri R, Normant E, Haigis MC, Manning BD, Wong KK, Macleod KF, Cichowski K (2011) Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20(3):400–413. doi:10.1016/j.ccr.2011.08.014
68. Asghar U, Hawkes E, Cunningham D (2010) Predictive and prognostic biomarkers for targeted therapy in metastatic colorectal cancer. Clin Colorectal Cancer 9(5):274–281. doi:10.3816/CCC.2010.n.040
69. Holderfield M, Deuker MM, McCormick F, McMahon M (2014) Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 14(7):455–467. doi:10.1038/nrc3760
70. Yuan ZX, Wang XY, Qin QY, Chen DF, Zhong QH, Wang L, Wang JP (2013) The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis. PLoS One 8(6):e65995. doi:10.1371/journal.pone.0065995
71. Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, Liao X, Waldron L, Hoshida Y, Huttenhower C, Chan AT, Giovannucci E, Fuchs C, Ogino S (2012) Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 61(6):847–854. doi:10.1136/gutjnl-2011-300865
72. 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(7):787–793. doi:10.1038/ng1834
73. Lochhead P, Kuchiba A, Imamura Y, Liao X, Yamauchi M, Nishihara R, Qian ZR, Morikawa T, Shen J, Meyerhardt JA, Fuchs CS, Ogino S (2013) Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 105(15):1151–1156. doi:10.1093/jnci/djt173
74. Tol J, Nagtegaal ID, Punt CJ (2009) BRAF mutation in metastatic colorectal cancer. N Engl J Med 361(1):98–99. doi:10.1056/NEJMc0904160
75. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P (2011) Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol Off J Eur Soc Med Oncol ESMO 22(7):1535–1546. doi:10.1093/annonc/mdq632
76. Ince WL, Jubb AM, Holden SN, Holmgren EB, Tobin P, Sridhar M, Hurwitz HI, Kabbinavar F, Novotny WF, Hillan KJ, Koeppen H (2005) Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97(13):981–989. doi:10.1093/jnci/dji174
77. Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, Freed E, Meyerhardt JA, Saridaki Z, Georgoulias V, Finkelstein D, Fuchs CS, Kulke MH, Shivdasani RA (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101(3):465–472. doi:10.1038/sj.bjc.6605164
78. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol Off J Am Soc Clin Oncol 29(15):2011–2019. doi:10.1200/JCO.2010.33.5091
79. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762. doi:10.1016/S1470-2045(10)70130-3
80. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 26(35):5705–5712. doi:10.1200/JCO.2008.18.0786
81. Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ, Schostack K, Simcox ME, Kopetz S, Heimbrook D, Lestini B, Bollag G, Su F (2012) Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res 72(3):779–789. doi:10.1158/0008-5472.CAN-11-2941
82. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Lee RJ, Nolop KB, Saltz L (2010) PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. ASCO Meeting Abstracts 28(15_suppl):3534
83. 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(7387):100–103. doi:10.1038/nature10868
84. 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(3):227–235. doi:10.1158/2159-8290.CD-11-0341
85. 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 Off J Am AssocCancer Res 19(10):2688–2698. doi:10.1158/1078-0432.CCR-12-2556
86. Mao M, Tian F, Mariadason JM, Tsao CC, Lemos R Jr, Dayyani F, Gopal YN, Jiang ZQ, 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 Off J Am Assoc Cancer Res 19(3):657–667. doi:10.1158/1078-0432.CCR-11-1446
87. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PA, Smith PD, Cook SJ (2011) Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal 4(166):ra17. doi:10.1126/scisignal.2001752
88. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M, Michelucci A, Pfanner E, Brunetti I, Lupi C, Antoniotti C, Bergamo F, Lonardi S, Zagonel V, Simi P, Fontanini G, Falcone A (2014) FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer 50(1):57–63. doi:10.1016/j.ejca.2013.08.024
89. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562. doi:10.1038/nrc2664
90. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69(5):1851–1857. doi:10.1158/0008-5472.CAN-08-2466
91. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554. doi:10.1126/science.1096502
92. Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol Off J Am Soc Clin Oncol 28(6):1075–1083. doi:10.1200/JCO.2009.25.3641
93. Amatu A, Bencardino K, Sartore-Bianchi A, Siena S (2013) Aspirin for colorectal cancer with PIK3CA mutations: the rising of the oldest targeted therapy? Ann Transl Med 1(2):12. doi:10.3978/j.issn. 2305-5839.2013.01.03
94. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S (2012) Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367(17):1596–1606. doi:10.1056/NEJMoa1207756
95. Day FL, Jorissen RN, Lipton L, Mouradov D, Sakthianandeswaren A, Christie M, Li S, Tsui C, Tie J, Desai J, Xu ZZ, Molloy P, Whitehall V, Leggett BA, Jones IT, McLaughlin S, Ward RL, Hawkins NJ, Ruszkiewicz AR, Moore J, Busam D, Zhao Q, Strausberg RL, Gibbs P, Sieber OM (2013) PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res 19(12):3285–3296. doi:10.1158/1078-0432.CCR-12-3614
96. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532. doi:10.1056/NEJM198809013190901
97. Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13(1):11–26. doi:10.1038/nrc3419
98. Mologni L, Dekhil H, Ceccon M, Purgante S, Lan C, Cleris L, Magistroni V, Formelli F, Gambacorti-Passerini CB (2010) Colorectal tumors are effectively eradicated by combined inhibition of {beta}-catenin, KRAS, and the oncogenic transcription factor ITF2. Cancer Res 70(18):7253–7263. doi:10.1158/0008-5472.CAN-10-1108
99. Takahashi-Yanaga F, Kahn M (2010) Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res Off J Am Assoc Cancer Res 16(12):3153–3162. doi:10.1158/1078-0432.CCR-09-2943
100. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115. doi:10.1038/nature05384
101. Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, Moon YC, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorgyi E, Gallinger S, Dick JE, O’Brien CA (2014) Self-renewal as a therapeutic target in human colorectal cancer. Nat Med 20(1):29–36. doi:10.1038/nm.3418
102. Bottsford-Miller JN, Coleman RL, Sood AK (2012) Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol Off J Am Soc Clin Oncol 30(32):4026–4034. doi:10.1200/JCO.2012.41.9242
103. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. doi:10.1056/NEJM197111182852108
104. Loges S, Mazzone M, Hohensinner P, Carmeliet P (2009) Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15(3):167–170. doi:10.1016/j.ccr.2009.02.007
105. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. doi:10.1056/NEJMoa032691
106. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol Off J Am Soc Clin Oncol 26(12):2013–2019. doi:10.1200/JCO.2007.14.9930
107. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera I, Bendahmane B, Andre T, Kubicka S, Investigators MLS (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14(1):29–37. doi:10.1016/S1470-2045(12)70477-1
108. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB, 3rd, Eastern Cooperative Oncology Group Study E (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol Off J Am Soc Clin Oncol 25(12):1539–1544. doi:10.1200/JCO.2006.09.6305
109. Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, Waterkamp D, Tabernero J (2013) Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 18(9):1004–1012. doi:10.1634/theoncologist. 2013-0107
110. Welch S, Spithoff K, Rumble RB, Maroun J, Gastrointestinal Cancer Disease Site G (2010) Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol Off J Eur Soc Med Oncol ESMO 21(6):1152–1162. doi:10.1093/annonc/mdp533
111. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol Off J Am Soc Clin Oncol 30(28):3499–3506. doi:10.1200/JCO.2012.42.8201
112. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D, Group CS (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312. doi:10.1016/S0140-6736(12)61900-X
113. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Borger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360(6):563–572. doi:10.1056/NEJMoa0808268
114. Longo R, Gasparini G (2007) Challenges for patient selection with VEGF inhibitors. Cancer Chemother Pharmacol 60(2):151–170. doi:10.1007/s00280-006-0403-6
115. Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26(5):605–622. doi:10.1016/j.ccell.2014.10.006
116. Tian S, Simon I, Moreno V, Roepman P, Tabernero J, Snel M, van’t Veer L, Salazar R, Bernards R, Capella G (2013) A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut 62(4):540–549. doi:10.1136/gutjnl-2012-302423
117. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404):537–540. doi:10.1038/nature11219
118. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D, Bardelli A (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536. doi:10.1038/nature11156
119. Hobor S, Van Emburgh BO, Crowley E, Misale S, Di Nicolantonio F, Bardelli A (2014) TGFalpha and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells. Clin Cancer Res Off J Am Assoc Cancer Res 20(24):6429–6438. doi:10.1158/1078-0432.CCR-14-0774
120. Tougeron D, Cortes U, Ferru A, Villalva C, Silvain C, Tourani JM, Levillain P, Karayan-Tapon L (2013) Epidermal growth factor receptor (EGFR) and KRAS mutations during chemotherapy plus anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer. Cancer Chemother Pharmacol 72(2):397–403. doi:10.1007/s00280-013-2211-0
121. Esposito C, Rachiglio AM, La Porta ML, Sacco A, Roma C, Iannaccone A, Tatangelo F, Forgione L, Pasquale R, Barbaro A, Botti G, Ciardiello F, Normanno N (2013) The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies. Cancer Biol Ther 14(12):1143–1146. doi:10.4161/cbt.26340
122. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Cora D, Di Nicolantonio F, Buscarino M, Petti C, Ribero D, Russolillo N, Muratore A, Massucco P, Pisacane A, Molinaro L, Valtorta E, Sartore-Bianchi A, Risio M, Capussotti L, Gambacorta M, Siena S, Medico E, Sapino A, Marsoni S, Comoglio PM, Bardelli A, Trusolino L (2011) A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1(6):508–523. doi:10.1158/2159-8290.CD-11-0109
123. Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, Pujara K, Guillory J, Edgar KA, Janakiraman V, Scholz RP, Bowman KK, Lorenzo M, Li H, Wu J, Yuan W, Peters BA, Kan Z, Stinson J, Mak M, Modrusan Z, Eigenbrot C, Firestein R, Stern HM, Rajalingam K, Schaefer G, Merchant MA, Sliwkowski MX, de Sauvage FJ, Seshagiri S (2013) Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23(5):603–617. doi:10.1016/j.ccr.2013.04.012
124. Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, Sliwkowski MX, Harari PM (2013) Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res 73(2):824–833. doi:10.1158/0008-5472.CAN-12-1611
125. Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA Jr, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S (2013) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3(6):658–673. doi:10.1158/2159-8290.CD-12-0558
126. Huang F, Xu LA, Khambata-Ford S (2012) Correlation between gene expression of IGF-1R pathway markers and cetuximab benefit in metastatic colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res 18(4):1156–1166. doi:10.1158/1078-0432.CCR-11-1135
127. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14(9):985–990. doi:10.1038/nm.1789
128. Schwarzenbach H, Hoon DS, Pantel K (2011) Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11(6):426–437. doi:10.1038/nrc3066
129. Beaver JA, Jelovac D, Balukrishna S, Cochran RL, Croessmann S, Zabransky DJ, Wong HY, Valda Toro P, Cidado J, Blair BG, Chu D, Burns T, Higgins MJ, Stearns V, Jacobs L, Habibi M, Lange J, Hurley PJ, Lauring J, VanDenBerg DA, Kessler J, Jeter S, Samuels ML, Maar D, Cope L, Cimino-Mathews A, Argani P, Wolff AC, Park BH (2014) Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 20(10):2643–2650. doi:10.1158/1078-0432.CCR-13-2933
130. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497(7447):108–112. doi:10.1038/nature12065
131. Mohan S, Heitzer E, Ulz P, Lafer I, Lax S, Auer M, Pichler M, Gerger A, Eisner F, Hoefler G, Bauernhofer T, Geigl JB, Speicher MR (2014) Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing. PLoS Genet 10(3):e1004271. doi:10.1371/journal.pgen.1004271