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Plasticity of Resistance and Sensitivity to Anti-Epidermal Growth Factor Receptor Inhibitors in Metastatic Colorectal Cancer

  • Andrea Sartore-BianchiEmail author
  • Salvatore Siena
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer mortality worldwide. Survival in the metastatic setting has been gradually improved by the addition to cytotoxic chemotherapy of agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in differing pathways of carcinogenesis. The knowledge of molecular abnormalities underlying colorectal tumourigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced in recent years by comprehensive sequencing studies. From these genome-scale analyses, we know that a handful of genes are commonly affected by somatic mutations, whereas recurrent copy-number alterations and chromosomal translocations are rarer in this disease. Even though some of these molecular abnormalities make genes acting as drivers of cancer progression, translation of this recognition for therapeutic purposes is still limited, encompassing only as standard of care the exclusion of RAS-mutated cancers for better selecting patients to candidate to EGFR-targeted therapy with monoclonal antibodies. However, the effort of ameliorating molecular selection should not be considered exhausted by demonstration of RAS and BRAF-induced resistance, as the genomic landscape of response to EGFR blockade has been demonstrated to be wider and dynamically multifaceted. In this chapter we will review main molecular biomarkers of de novo (primary) and acquired (secondary) resistance to EGFR-targeted monoclonal antibodies in metastatic CRC and discuss therapeutic implications.

Keywords

Cetuximab Colorectal cancer EGFR Liquid biopsy Panitumumab RAS 

References

  1. 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) J Clin Oncol 26:1626–1634CrossRefGoogle Scholar
  2. Arena S, Bellosillo B, Siravegna G, Martínez A, Cañadas I, Lazzari L, Ferruz N, Russo M, Misale S, González I, Iglesias M, Gavilan E, Corti G, Hobor S, Crisafulli G, Salido M, Sánchez J, Dalmases A, Bellmunt J, De Fabritiis G, Rovira A, Di Nicolantonio F, Albanell J, Bardelli A, Montagut C (2015) Clin Cancer Res 21:2157–2166CrossRefGoogle Scholar
  3. Bardelli A, Siena S (2010) J Clin Oncol 28:1254–1261CrossRefGoogle Scholar
  4. 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, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S (2013) Cancer Discov 3:658–673CrossRefGoogle Scholar
  5. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A (2007) Cancer Res 67:2643–2648CrossRefGoogle Scholar
  6. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Corà 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) Cancer Discov 1:508–523CrossRefGoogle Scholar
  7. Bertotti A, Papp E, Jones S, Adleff V, Anagnostou V, Lupo B, Sausen M, Phallen J, Hruban CA, Tokheim C, Niknafs N, Nesselbush M, Lytle K, Sassi F, Cottino F, Migliardi G, Zanella ER, Ribero D, Russolillo N, Mellano A, Muratore A, Paraluppi G, Salizzoni M, Marsoni S, Kragh M, Lantto J, Cassingena A, Li QK, Karchin R, Scharpf R, Sartore-Bianchi A, Siena S, Diaz LA, Trusolino L, Velculescu VE (2015) Nature 526:263–267CrossRefGoogle Scholar
  8. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong S-M, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SKN, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih L-M, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang T-L, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA (2014) Sci Transl Med 6:224ra24CrossRefGoogle Scholar
  9. Cancer Genome Atlas Network (2012) Nature 487:330–337CrossRefGoogle Scholar
  10. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, Schwartz L, Klimstra DS, Fridman D, Kelsen DP, Saltz LB (2005) J Clin Oncol 23:1803–1810CrossRefGoogle Scholar
  11. Ciombor KK, Wu C, Goldberg RM (2015) Annu Rev Med 66:83–95CrossRefGoogle Scholar
  12. Corcoran RB, Atreya CE, Falchook GS, Infante JR, Hamid O, Messersmith WA, Daud A, Kwak EL, Ryan D, Kurzrock R, Sun P, Cunningham EA, Orford KW, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S (2014) J Clin Oncol 32:5sGoogle Scholar
  13. Cremolini C, Di Bartolomeo M, Amatu A, Antoniotti C, Moretto R, Berenato R, Perrone F, Tamborini E, Aprile G, Lonardi S, Sartore-Bianchi A, Fontanini G, Milione M, Lauricella C, Siena S, Falcone A, de Braud F, Loupakis F, Pietrantonio F (2015) Ann Oncol Off J Eur Soc Med Oncol 26:2092–2097CrossRefGoogle Scholar
  14. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) N Engl J Med 351:337–345CrossRefGoogle Scholar
  15. Day E, Poulogiannis G, McCaughan F, Mulholland S, Arends MJ, Ibrahim AEK, Dear PH (2013) Int J Exp Pathol 94:203–211PubMedPubMedCentralGoogle Scholar
  16. 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) Lancet Oncol. 11:753–762CrossRefGoogle Scholar
  17. 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) J Clin Oncol 26:5705–5712CrossRefGoogle Scholar
  18. Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S (1995) Clin Cancer Res 1:147–154PubMedGoogle Scholar
  19. Douillard J-Y, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD (2013) N Engl J Med 369:1023–1034CrossRefGoogle Scholar
  20. 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) Cancer Biol Ther 14:1143–1146CrossRefGoogle Scholar
  21. Fisher R, Pusztai L, Swanton C (2013) Br J Cancer 108:479–485CrossRefGoogle Scholar
  22. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran S-E, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes H-G, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S (2014) Lancet Oncol 15:1065–1075CrossRefGoogle Scholar
  23. Ingold Heppner B, Behrens H-M, Balschun K, Haag J, Krüger S, Becker T, Röcken C (2014) Br J Cancer 111:1977–1984CrossRefGoogle Scholar
  24. Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, Pujara K, Guillory J, Edgar KA, Janakiraman V, Scholz R-P, 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) Cancer Cell 23:603–617CrossRefGoogle Scholar
  25. Kavuri SM, Jain N, Galimi F, Cottino F, Leto SM, Migliardi G, Searleman AC, Shen W, Monsey J, Trusolino L, Jacobs SA, Bertotti A, Bose R (2015) Cancer Discov 5:832–841CrossRefGoogle Scholar
  26. Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Villalobos Valencia R, Srinivasan K, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E (2016) J Clin Oncol 34:642–642CrossRefGoogle Scholar
  27. Leto SM, Trusolino L (2014) J Mol Med Berl Ger 92:709–722CrossRefGoogle Scholar
  28. Lièvre A, Bachet J-B, Le Corre D, Boige V, Landi B, Emile J-F, Côté J-F, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) Cancer Res 66:3992–3995CrossRefGoogle Scholar
  29. Liska D, Chen C-T, Bachleitner-Hofmann T, Christensen JG, Weiser MR (2011) Clin Cancer Res 17:472–482CrossRefGoogle Scholar
  30. Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, Saletti P, De Dosso S, Spitale A, Tejpar S, Kalogeras KT, Mazzucchelli L, Frattini M, Cappuzzo F (2013) Br J Cancer 108:668–675CrossRefGoogle Scholar
  31. 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 C-T, 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) Nature 486:532–536CrossRefGoogle Scholar
  32. Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A (2014) Cancer Discov 4:1269–1280CrossRefGoogle Scholar
  33. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Seshagiri S, Somasekar S, Serrano S, Himmelbauer H, Bellmunt J, Rovira A, Settleman J, Bosch F, Albanell J (2012) Nat Med 18:221–223CrossRefGoogle Scholar
  34. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A (2005) Lancet Oncol 6:279–286CrossRefGoogle Scholar
  35. Moroni M, Veronese S, Sartore-Bianchi A, Artale S, Siena S (2008) Target Oncol 3:127–130CrossRefGoogle Scholar
  36. Newhall K, Price T, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Ogbagabriel S, Boedigheimer M, Sexson S, Zhang K, Murugappan S, Sidhu R (2014) Ann Oncol 25:ii109CrossRefGoogle Scholar
  37. Nunes M, Vrignaud P, Vacher S, Richon S, Lièvre A, Cacheux W, Weiswald L-B, Massonnet G, Chateau-Joubert S, Nicolas A, Dib C, Zhang W, Watters J, Bergstrom D, Roman-Roman S, Bièche I, Dangles-Marie V (2015) Cancer Res 75:1560–1566CrossRefGoogle Scholar
  38. Park DI, Kang MS, Oh SJ, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Han WK, Kim H, Ryu SH, Sepulveda AR (2007) Int J Color Dis 22:491–497CrossRefGoogle Scholar
  39. Peeters M, Kafatos G, Taylor A, Gastanaga VM, Oliner KS, Hechmati G, Terwey J-H, van Krieken JH (2015) Eur J Cancer Oxford Engl 51:1704–1713CrossRefGoogle Scholar
  40. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, De Roock W, Capoen A, Debiec-Rychter M, Van Laethem J-L, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) Clin Cancer Res 14:5869–5876CrossRefGoogle Scholar
  41. Prior IA, Lewis PD, Mattos C (2012) Cancer Res 72:2457–2467CrossRefGoogle Scholar
  42. Raghav K, Morris V, Tang C, Morelli P, Amin HM, Chen K, Manyam GC, Broom B, Overman MJ, Shaw K, Meric-Bernstam F, Maru D, Menter D, Ellis LM, Eng C, Hong D, Kopetz S (2016) Oncotarget 7:54627–54631CrossRefGoogle Scholar
  43. Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P (2009) J Clin Oncol 27:5931–5937CrossRefGoogle Scholar
  44. Richman SD, Southward K, Chambers P, Cross D, Barrett J, Hemmings G, Taylor M, Wood H, Hutchins G, Foster JM, Oumie A, Spink KG, Brown SR, Jones M, Kerr D, Handley K, Gray R, Seymour M, Quirke P (2016) J Pathol 238:562–570CrossRefGoogle Scholar
  45. Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, Sorich MJ (2015) Br J Cancer 112:1888–1894CrossRefGoogle Scholar
  46. Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G (2012) PLoS One 7:e47054CrossRefGoogle Scholar
  47. Saltz LB, Meropol NJ, Loehrer PJ, Needle MN, Kopit J, Mayer RJ (2004) J Clin Oncol 22:1201–1208CrossRefGoogle Scholar
  48. Sánchez-Martín FJ, Bellosillo B, Gelabert-Baldrich M, Dalmases A, Cañadas I, Vidal J, Martinez A, Argilés G, Siravegna G, Arena S, Koefoed K, Visa L, Arpí O, Horak ID, Iglesias M, Stroh C, Kragh M, Rovira A, Albanell J, Tabernero J, Bardelli A, Montagut C (2016) Clin Cancer Res 22:3260–3267CrossRefGoogle Scholar
  49. Sartore-Bianchi A, Moroni M, Veronese S, Carnaghi C, Bajetta E, Luppi G, Sobrero A, Barone C, Cascinu S, Colucci G, Cortesi E, Nichelatti M, Gambacorta M, Siena S (2007) J Clin Oncol 25:3238–3245CrossRefGoogle Scholar
  50. Sartore-Bianchi A, Fieuws S, Veronese S, Moroni M, Personeni N, Frattini M, Torri V, Cappuzzo F, Vander Borght S, Martin V, Skokan M, Santoro A, Gambacorta M, Tejpar S, Varella-Garcia M, Siena S (2012) J Clin Pathol 65:218–223CrossRefGoogle Scholar
  51. Sartore-Bianchi A, Loupakis F, Argilés G, Prager GW (2016a) Ann. Oncol 27:1456–1466CrossRefGoogle Scholar
  52. Sartore-Bianchi A, Siena S, Tonini G, Bardelli A, Santini D (2016b) Cancer Treat Rev 51:54–62CrossRefGoogle Scholar
  53. Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, Martinelli E, Troiani T, Ciardiello F, Racca P, Bertotti A, Siravegna G, Torri V, Amatu A, Ghezzi S, Marrapese G, Palmeri L, Valtorta E, Cassingena A, Lauricella C, Vanzulli A, Regge D, Veronese S, Comoglio PM, Bardelli A, Marsoni S, Siena S (2016c) Lancet Oncol 17:738–746CrossRefGoogle Scholar
  54. Sartore-Bianchi A, Valtorta E, Amatu A, Veronese S, Lauricella C, Bonazzina E, Siravegna G, Truini M, Bardelli A, Siena S (2016d) ESMO Open 1:e000079CrossRefGoogle Scholar
  55. Scartozzi M, Bearzi I, Mandolesi A, Pierantoni C, Loupakis F, Zaniboni A, Negri F, Quadri A, Zorzi F, Galizia E, Berardi R, Biscotti T, Labianca R, Masi G, Falcone A, Cascinu S (2009) BMC Cancer 9:303CrossRefGoogle Scholar
  56. Scartozzi M, Mandolesi A, Giampieri R, Bittoni A, Pierantoni C, Zaniboni A, Galizia E, Giustini L, Silva RR, Bisonni R, Berardi R, Biscotti T, Biagetti S, Bearzi I, Cascinu S (2011) Oncologist 16:53–60CrossRefGoogle Scholar
  57. Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, Nagtegaal ID, Beets-Tan RG, Arnold D, Ciardiello F, Hoff P, Kerr D, Köhne CH, Labianca R, Price T, Scheithauer W, Sobrero A, Tabernero J, Aderka D, Barroso S, Bodoky G, Douillard JY, El Ghazaly H, Gallardo J, Garin A, Glynne-Jones R, Jordan K, Meshcheryakov A, Papamichail D, Pfeiffer P, Souglakos I, Turhal S, Cervantes A (2012) Ann Oncol 23:2479–2516CrossRefGoogle Scholar
  58. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon J-L, Hecht JR, Yu H, Oliner KS, Go WY (2014) J Clin Oncol 32:2240–2247CrossRefGoogle Scholar
  59. Seo AN, Kwak Y, Kim D-W, Kang S-B, Choe G, Kim WH, Lee HS (2014) PLoS One 9:e98528CrossRefGoogle Scholar
  60. Siegel RL, Miller KD, Jemal A (2017) CA Cancer J Clin 67:7–30CrossRefGoogle Scholar
  61. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C, Lamba S, Hobor S, Avallone A, Valtorta E, Rospo G, Medico E, Motta V, Antoniotti C, Tatangelo F, Bellosillo B, Veronese S, Budillon A, Montagut C, Racca P, Marsoni S, Falcone A, Corcoran RB, Di Nicolantonio F, Loupakis F, Siena S, Sartore-Bianchi A, Bardelli A (2015) Nat Med 21:795–801CrossRefGoogle Scholar
  62. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS (2015) Ann Oncol 26:13–21CrossRefGoogle Scholar
  63. Tannock IF, Hickman JA (2016) N Engl J Med 375:1289–1294CrossRefGoogle Scholar
  64. Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, Gillet B, Gongora C, Dechelotte P, Robert B, Del Rio M, Lamy P-J, Bibeau F, Nouaille M, Loriot V, Jarrousse A-S, Molina F, Mathonnet M, Pezet D, Ychou M (2014) Nat Med 20:430–435CrossRefGoogle Scholar
  65. Trusolino L, Bertotti A, Comoglio PM (2010) Nat Rev Mol Cell Biol 11:834–848CrossRefGoogle Scholar
  66. Ushijima T, Yoshino T (2016) Cancer Res 76:6443–6444CrossRefGoogle Scholar
  67. Valtorta E, Misale S, Sartore-Bianchi A, Nagtegaal ID, Paraf F, Lauricella C, Dimartino V, Hobor S, Jacobs B, Ercolani C, Lamba S, Scala E, Veronese S, Laurent-Puig P, Siena S, Tejpar S, Mottolese M, Punt CJA, Gambacorta M, Bardelli A, Di Nicolantonio F (2013) Int J Cancer 133:1259–1265CrossRefGoogle Scholar
  68. Valtorta E, Martino C, Sartore-Bianchi A, Penaullt-Llorca F, Viale G, Risio M, Rugge M, Grigioni W, Bencardino K, Lonardi S, Zagonel V, Leone F, Noe J, Ciardiello F, Pinto C, Labianca R, Mosconi S, Graiff C, Aprile G, Frau B, Garufi C, Loupakis F, Racca P, Tonini G, Lauricella C, Veronese S, Truini M, Siena S, Marsoni S, Gambacorta M (2015) Mod Pathol 28:1481–1491CrossRefGoogle Scholar
  69. Van Cutsem E, Köhne C-H, Láng 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) J Clin Oncol 29:2011–2019CrossRefGoogle Scholar
  70. Van Cutsem E, Lenz H-J, Köhne C-H, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F (2015) J Clin Oncol 33:692–700CrossRefGoogle Scholar
  71. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D’Hoore A, Diaz-Rubio E, Douillard J-Y, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Köhne C-H, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund P, Oyen WJG, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D (2016) Ann Oncol 27:1386–1422CrossRefGoogle Scholar
  72. Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio F, Siena S, Bardelli A (2014) Mol Oncol 8:1084–1094CrossRefGoogle Scholar
  73. Van Emburgh BO, Arena S, Siravegna G, Lazzari L, Crisafulli G, Corti G, Mussolin B, Baldi F, Buscarino M, Bartolini A, Valtorta E, Vidal J, Bellosillo B, Germano G, Pietrantonio F, Ponzetti A, Albanell J, Siena S, Sartore-Bianchi A, Di Nicolantonio F, Montagut C, Bardelli A (2016) Nat Commun 7:13665CrossRefGoogle Scholar
  74. Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Mahoney MR, O’Neil BH, Shaw JE, Polite BN, Hochster HS, Atkins JN, Goldberg RM, Mayer RJ, Schilsky RL, Bertagnolli MM, Blanke CD, Alliance CLGB, SWOG, ECOG (2014) J Clin Oncol 32:5sCrossRefGoogle Scholar
  75. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013) Science 339:1546–1558CrossRefGoogle Scholar
  76. 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, Jänne PA (2011) Sci Transl Med 3:99ra86CrossRefGoogle Scholar
  77. Yuan Z-X, Wang X-Y, Qin Q-Y, Chen D-F, Zhong Q-H, Wang L, Wang J-P (2013) PLoS One 8:e65995CrossRefGoogle Scholar
  78. Zeng Z-S, Weiser MR, Kuntz E, Chen C-T, Khan SA, Forslund A, Nash GM, Gimbel M, Yamaguchi Y, Culliford AT, D’Alessio M, Barany F, Paty PB (2008) Cancer Lett 265:258–269CrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Niguarda Cancer CenterGrande Ospedale Metropolitano NiguardaMilanItaly
  2. 2.Dipartimento di Oncologia ed Emato-OncologiaUniversità degli Studi di MilanoMilanItaly

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