Anti-EGFR Therapy to Treat Metastatic Colorectal Cancer: Not for All

  • Marta MartinsEmail author
  • André Mansinho
  • Raquel Cruz-Duarte
  • Soraia Lobo Martins
  • Luís Costa
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1110)


The development of monoclonal antibodies (mAbs) cetuximab and panitumumab, which target the transmembrane protein epidermal growth factor receptor (EGFR), mark a major step forward in the treatment of metastatic colorectal cancer (mCRC). However, this therapeutic progress proved to be effective only in a very restricted subset of patients. Although several mechanisms of resistance, both primary and acquired, have been identified, the only established predictive tumour biomarker for the treatment of mCRC patients is the RAS mutational status. RAS activating mutations predict a lack of response to these therapies while low levels of primary resistance characterize RAS wild type (WT) patients (only about 15%). However, even WT patients that initially respond to anti-EGFR therapy, eventually undergo tumour progression. In this context, there is still more to be done in the search for effective predictive markers with therapeutic applicability. In this chapter, we provide an overview on the mechanisms that contribute to resistance to EGFR-targeted therapy and highlight what is still missing in our understanding of these molecular mechanisms and approaches to overcome them.


Colorectal cancer Epidermal growth factor receptor Primary resistance Secondary resistance Targeted therapy 


  1. Al-Marrawi MY, Saroya BS, Brennan MC, Yang Z, Dykes TM, El-Deiry WS (2013) Off-label use of cetuximab plus sorafenib and panitumumab plus regorafenib to personalize therapy for a patient with V600E BRAF-mutant metastatic colon cancer. Cancer Biol Ther 14:703–710. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andersen NJ, Boguslawski EB, Kuk CY, Chambers CM, Duesbery NS (2015) Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts. Int J Oncol 47:71–80. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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) Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res 21:2157–2166. CrossRefPubMedGoogle Scholar
  4. Atreya CE, Van Cutsem E, Bendell JC, Andre T, Schellens JHM, Gordon MS, Jackson McRee A, O’Dwyer PJ, Muro K, Tabernero J, van Geel R, Sidhu R, Greger JG, Rangwala FA, Motw M, Wu Y, Orford KW, Corcoran RB (2015) Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). J Clin Pathol 33(15_suppl):103. CrossRefGoogle Scholar
  5. Barber TD, Vogelstein B, Kinzler KW, Velculescu VE (2004) Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351:2883. CrossRefPubMedGoogle Scholar
  6. 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) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3:658–673. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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) A molecularly annotated platform of patient- derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1:508–523. CrossRefPubMedGoogle Scholar
  8. Bianco R, Rosa R, Damiano V, Daniele G, Gelardi T, Garofalo S, Tarallo V, De Falco S, Melisi D, Benelli R, Albini A, Ryan A, Ciardiello F, Tortora G (2008) Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res 14:5069–5080. CrossRefPubMedGoogle Scholar
  9. 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 22:1535–1546. CrossRefPubMedGoogle Scholar
  10. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, De Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671. CrossRefGoogle Scholar
  11. Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689PubMedGoogle Scholar
  12. Bouchahda M, Karaboué A, Saffroy R, Innominato P, Gorden L, Guettier C, Adam R, Lévi F (2010) Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis. Cancer Chemother Pharmacol 66:605–609. CrossRefPubMedGoogle Scholar
  13. Buck E, Eyzaguirre A, Barr S, Thompson S, Sennello R, Young D, Iwata KK, Gibson NW, Cagnoni P, Haley JD (2007) Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther 6:532–541. CrossRefPubMedGoogle Scholar
  14. Campanella C, Mottolese M, Cianciulli A, Torsello A, Merola R, Sperduti I, Melucci E, Conti S, Diodoro MG, Zeuli M, Paoletti G, Cognetti F, Garufi C (2010) Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab. J Transl Med 8:36. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Cappuzzo F, Finocchiaro G, Rossi E, Jänne PA, Carnaghi C, Calandri C, Bencardino K, Ligorio C, Ciardiello F, Pressiani T, Destro A, Roncalli M, Crino L, Franklin WA, Santoro A, Varella-Garcia M (2008) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19:717–723. CrossRefPubMedGoogle Scholar
  16. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, John Simes R, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au H-J, Langer C, Moore MJ (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810. CrossRefPubMedGoogle Scholar
  18. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174. CrossRefGoogle Scholar
  19. 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
  20. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della PP, Dias-Santagata D, Hung KE, Flaherty KT, Piris A, Wargo JA, Settleman J, Mino-Kenudson M, Engelman JA (2012) EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2:227–235. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Costa-Cabral S, Brough R, Konde A, Aarts M, Campbel J, Marinari E, Riffell J, Bardelli A, Torrance C, Lord CJ, Ashworth A (2016) CDK1 is a synthetic lethal target for KRAS mutant tumours. PLoS One 11:e0149099. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6:184–192. CrossRefGoogle Scholar
  23. 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) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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 (2010a) 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 11:753–762. CrossRefPubMedPubMedCentralGoogle Scholar
  25. De Roock W, Jonker DJ, Di NF, Sartore-bianchi A, Simes J (2010b) Association of KRAS p. G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. J Am Med Assoc 304:1812–1820. CrossRefGoogle Scholar
  26. 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 486:537–540. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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 26:5705–5712. CrossRefPubMedGoogle Scholar
  28. Douillard JY, Siena S, Cassidy J, 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, Oliner KS, Tian Y, Xu F, Sidhu R (2014) Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25:1346–1355. CrossRefPubMedGoogle Scholar
  29. 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 136:E359–E386. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fernández-Medarde A, Santos E (2011) Ras in cancer and developmental diseases. Genes and Cancer 2:344–358. CrossRefPubMedGoogle Scholar
  31. Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F, Mazzucchelli L (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Gazdar A (2009) Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 28:1–14. CrossRefGoogle Scholar
  33. Gomez-Roca CA, Delord J, Robert C, Hidalgo M, von Moos R, Arance A, Elez E, Michel D, Seroutou A, Demuth T, Tabernero J (2014) 535Pencorafenib (Lgx818), an oral braf inhibitor, in patients (Pts) with Braf V600E metastatic colorectal cancer (Mcrc): results of dose expansion in an open-label, phase 1 study. Ann Oncol 25:iv182–iv183. CrossRefGoogle Scholar
  34. 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
  35. Heinemann V, Von Weikersthal LF, Decker T, Kiani A, Vehling-kaiser U, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffk H, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S, Jena U (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 15:1065–1075. CrossRefPubMedGoogle Scholar
  36. Huijberts S, Schellens JHM, Fakih M, Peeters M, Kopetz S, Grothey A, Van Cutsem E, Wasan HS, Desai J, Ciardiello F, Yoshino T, Maharry K, Gollerkeri A, Tabernero J (2017) BEACON CRC (binimetinib [BINI], encorafenib [ENCO], and cetuximab [CTX] combined to treat BRAF-mutant metastatic colorectal cancer [mCRC]): a multicenter, rando.mized, open-label, three-arm phase III study of ENCO plus CTX plus or minus BINI vs irinotecan. J Clin Oncol 35(15 Suppl).
  37. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354. CrossRefGoogle Scholar
  38. 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, Pénault-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 27:5068–5074. CrossRefPubMedGoogle Scholar
  39. 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, deSauvage FJ, Seshagiri S (2013) Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23:603–617. CrossRefPubMedGoogle Scholar
  40. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus SJ, Darjania L, Feng J, Chen JH, Li S, Li S, Long YO, Thach C, Liu Y, Zarieh A, Ely T, Kucharski JM, Kessler LV, Wu T, Yu K, Wang Y, Yao Y, Deng X, Zarrinkar PP, Brehmer D, Dhanak D, Lorenzi MV, Hu-Lowe D, Patricelli MP, Ren P, Liu Y (2018) Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172:578–589.e17. CrossRefPubMedGoogle Scholar
  41. Jia J, Niedzwiecki D, Uronis HE, Morse M, Zafar Y, Hsu SD, Bolch E, Nagy RJ, Lanman RB, Talasaz AA, Haley S, Nixon AB, Strickler JH (2018) A phase I/II trial of cabozantinib (C) with or without panitumumab (P) in patients (pts) with RAS wild-type (WT) metastatic colorectal cancer (mCRC): clinical outcomes in pts with MET amplification (amp) detected in blood. J Clin Oncol 36(15 Suppl):3555CrossRefGoogle Scholar
  42. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au H-J, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048. CrossRefGoogle Scholar
  43. Karapetis CS, Jonker D, Daneshmand M, Hanson JE, O’Callaghan CJ, Marginean C, Zalcberg JR, Simes J, Moore MJ, Tebbutt NC, Price TJ, Shapiro JD, Pavlakis N, Gibbs P, Van Hazel GA, Lee U, Haq R, Virk S, Tu D, Lorimer IAJ (2014) PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer-results from NCIC CTG/AGITG CO.17. Clin Cancer Res 20:744–753. CrossRefPubMedGoogle Scholar
  44. Kearns JD, Bukhalid R, Sevecka M, Tan G, Gerami-Moayed N, Werner SL, Kohli N, Burenkova O, Sloss CM, King AM, Fitzgerald JB, Nielsen UB, Wolf BB (2015) Enhanced targeting of the EGFR network with MM-151, an oligoclonal anti-egfr antibody therapeutic. Mol Cancer Ther 14:1625–1636. CrossRefPubMedGoogle Scholar
  45. 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, 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 25:3230–3237. CrossRefPubMedGoogle Scholar
  46. Kim JS, Kim JE, Kim K, Lee J, Park JO, Lim HY, Park YS, Kang WK, Kim ST (2017) The impact of cetuximab plus AKT- or mTOR-inhibitor in a patient-derived colon cancer cell model with wild-type RAS and PIK3CA mutation. J Cancer 8:2713–2719. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Kohl NE, Omer CA, Davide JP, Hamilton K, Koblan KS, Kral AM, Miller PJ, Mosser SD, O’neill TJ, Rands E, Schaber MD, Gibbs JB, Oliff A, Conner MW, Anthony NJ, Jane Desolms S, Giuliani EA, Gomez RP, Graham SL, Hartman GD, Anthony NJ (1995) Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1:792–797. CrossRefPubMedGoogle Scholar
  48. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa JPJ, 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
  49. Kopetz S, McDonough SL, Morris VK, Lenz HJ, Magliocco AM, Atreya CE, Diaz LA, Allegra CJ, Wang SE, Hanyoung Lieu C, Eckhardt SG, Semrad TJ, Kaberle K, Guthrie KA, Hochster HS (2017) Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer. J Clin Oncol 35(4 Suppl):520. CrossRefGoogle Scholar
  50. Krumbach R, Schüler J, Hofmann M, Giesemann T, Fiebig HH, Beckers T (2011) Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. Eur J Cancer 47:1231–1243. CrossRefPubMedGoogle Scholar
  51. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouché O, Reid J, Stone S, Penault-Llorca F (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27:5924–5930. CrossRefPubMedGoogle Scholar
  52. Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL (2009) Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 28:3801–3813. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Li Q, Zhang D, Chen X, He L, Li T, Xu X, Li M (2015) Nuclear PKM2 contributes to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer. Sci Rep 5:1–12. CrossRefGoogle Scholar
  54. Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, Papadimitriou CA, Murray S (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9:962–972. CrossRefPubMedGoogle Scholar
  55. Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A (2009) PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 27:2622–2629. CrossRefPubMedGoogle Scholar
  56. Macdonald JS, McCoy S, Whitehead RP, Iqbal S, Wade JL, Giguere JK, Abbruzzese JL (2005) A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs 23:485–487. CrossRefPubMedGoogle Scholar
  57. Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–465. CrossRefPubMedGoogle Scholar
  58. Mao C, Yang ZY, Hu XF, Chen Q, Tang JL (2012) PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol 23:1518–1525. CrossRefPubMedGoogle Scholar
  59. Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER, Buscarino M, Ribero D, Muratore A, Massucco P, Pisacane A, Risio M, Capussotti L, Marsoni S, Di Nicolantonio F, Bardelli A, Comoglio PM, Trusolino L, Bertotti A (2012) Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res 18:2515–2525. CrossRefGoogle Scholar
  60. 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 486:532–536. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Molinari F, Frattini M (2014) Functions and regulation of the PTEN gene in colorectal cancer. Front Oncol 3:1–8. CrossRefGoogle Scholar
  62. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Somasekar 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 18:221–223. CrossRefPubMedGoogle Scholar
  63. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286. CrossRefPubMedGoogle Scholar
  64. Nosho K, Kawasaki T, Longtine JA, Fuchs CS, Ohnishi M, Suemoto Y, Kirkner GJ, Zepf D, Yan L, Ogino S (2008) PIK3CA autation in colorectal cancer: relationship with genetic and epigenetic Alterations. Neoplasia 10:534–541. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Oda K, Matsuoka Y, Funahashi A, Kitano H (2005) A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 1:E1–E17. CrossRefGoogle Scholar
  66. Organ SL, Tsao MS (2011) An overview of the c-MET signaling pathway. Ther Adv Med Oncol 3:S7–S19. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548–551. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Patricelli MP, Janes MR, Li LS, Hansen R, Peters U, Kessler LV, Chen Y, Kucharski JM, Feng J, Ely T, Chen JH, Firdaus SJ, Babbar A, Ren P, Liu Y (2016) Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316–329. CrossRefPubMedGoogle Scholar
  69. Pedersen MW, Jacobsen HJ, Koefoed K, Hey A, Pyke C, Haurum JS, Kragh M (2010) Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res 70:588–597. CrossRefPubMedGoogle Scholar
  70. Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R, Wiezorek J (2013) Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol 31:759–765. CrossRefPubMedGoogle Scholar
  71. Perez EA, Hurvitz SA, Amler LC, Mundt KE, Ng V, Guardino E, Gianni L (2014) Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res 16:R50. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, De Roock W, Capoen A, Debiec-Rychter M, Van LJL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 14:5869–5876. CrossRefPubMedGoogle Scholar
  73. Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, Cabiddu M, Iacovelli R, Bossi I, Lonati V, Ghilardi M, De Braud F, Barni S (2015) Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer 51:587–594. CrossRefPubMedGoogle Scholar
  74. 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 483:100–104. CrossRefGoogle Scholar
  75. Rawlings JS (2004) The JAK/STAT signaling pathway. J Cell Sci 117:1281–1283. CrossRefPubMedGoogle Scholar
  76. Rommel C, Fruman DA (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13:140–156. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 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) Standardisation of EGFR FISH in colorectal cancer: results of an international interlaboratory reproducibility ring study. J Clin Pathol 65:218–223. CrossRefPubMedGoogle Scholar
  78. 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 69:1851–1857. CrossRefGoogle Scholar
  79. 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) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25:3238–3245. CrossRefPubMedGoogle Scholar
  80. 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 (2016) Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 17:738–746. CrossRefGoogle Scholar
  81. Scartozzi M, Bearzi I, Pierantoni C, Mandolesi A, Loupakis F, Zaniboni A, Catalano V, Quadri A, Zorzi F, Berardi R, Biscotti T, Labianca R, Falcone A, Cascinu S (2007) Nuclear factor-kB tumor expression predicts response and survival in irinotecan-refractory metastatic colorectal cancer treated with cetuximab-irinotecan therapy. J Clin Oncol 25:3930–3935. CrossRefPubMedGoogle Scholar
  82. 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) The Role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab. Oncologist 16:53–60. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS (2015) Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 26:13–21. CrossRefPubMedGoogle Scholar
  84. Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R, Attar A, Benichou J, Martin A, Morere JF, Raphael M, Penault-Llorca F, Breau JL, Fagard R, Khayat D, Wind P (2005) Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 16:102–108. CrossRefGoogle Scholar
  85. Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumagi A, Arjama M, Danielsen SA, Kryeziu K, Elez E, Tabernero J, Guinney J, Palmer HG, Nesbakken A, Kallioniemi O, Dienstmann R, Lothe RA (2018) Colorectal cancer consensus molecular subtypes translated to preclinical models uncover potentially targetable cancer cell dependencies. Clin Cancer Res 24:794–806. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Tabernero J, van Geel R, Guren TK, Yaeger RD, Spreafico A, Faris JE, Yoshino T, Yamada Y, Kim TW, Bendell J, Schuler M, Lenz HJ, Eskens F, Desai J, Hochster H, Avsar E, Demuth T, Sandor V, Elez E, Schellens J (2016) Phase 2 results: encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC). J Clin Oncol 34(15_suppl):3544. CrossRefGoogle Scholar
  87. Temraz S, Mukherji D, Shamseddine A (2015) Dual inhibition of MEK and PI3K pathway in KRAS and BRAF mutated colorectal cancers. Int J Mol Sci 16:22976–22988. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Thanki K, Edward Nicholls M, Gomez G, Gajjar A, James Senagore A, Rashidi L, Qiu S, Szabo C, Richard Hellmich M, Chao C (2017) Consensus molecular subtypes of colorectal cancer and their clinical implications. Int Biol Biomed J 3:105–111PubMedPubMedCentralGoogle Scholar
  89. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M (2014) The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis. Acta Oncol (Madr) 53:852–864. CrossRefGoogle Scholar
  90. Townsend A, Tebbutt N, Karapetis C, Cooper P, Singhal N, Yeend S, Pirc L, Joshi R, Hardingham J, Price T (2018) Phase IB/II study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in KRAS wild-type metastatic colorectal cancer. Clin Cancer Res 24:3838–3844. CrossRefPubMedGoogle Scholar
  91. Troiani T, Martinelli E, Napolitano S, Vitagliano D, Ciuffreda LP, Costantino S, Morgillo F, Capasso A, Sforza V, Nappi A, De Palma R, D’Aiuto E, Berrino L, Bianco R, Ciardiello F (2013) Increased TGF-α as a mechanism of acquired resistance to the anti-EGFR inhibitor cetuximab through EGFR-MET interaction and activation of MET signaling in colon cancer cells. Clin Cancer Res 19:6751–6765. CrossRefPubMedGoogle Scholar
  92. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T (2012) Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 30:1755–1762. CrossRefPubMedGoogle Scholar
  93. Vallböhmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA, Rhodes KE, Iqbal S, Danenberg KD, Lenz HJ (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23(16 Suppl):3551. CrossRefGoogle Scholar
  94. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon J-L, Van Laethem J-L, Maurel J, Richardson G, Wolf M, Amado RG (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664. CrossRefPubMedGoogle Scholar
  95. Van Cutsem E, Köhne CH, 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) 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 29:2011–2019. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, Davidenko I, Stephenson J, Elez E, Prenen H, Deng H, Tang R, McCaffery I, Oliner KS, Chen L, Gansert J, Loh E, Smethurst D, Tabernero J (2014) Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin Cancer Res 20:4240–4250. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, Han Van Krieken J, Ciardiello F (2015a) Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33:692–700. CrossRefPubMedGoogle Scholar
  98. Van Cutsem E, Atreya C, André T, Bendell J, Schellens J, Gordon M, McRee A, Yoshino T, Muro K, ODwyer P, Tabernero J, Middleton G, Ducreux M, van Geel R, Sidhu R, Greger J, Rangwala F, Liu Y, Wu Y, Mookerjee B, Corcoran R (2015b) Updated Results of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). Ann Oncol 26(Suppl 4):iv119. CrossRefGoogle Scholar
  99. Van Geel RMJM, Tabernero J, Elez E, Bendell JC, Spreafico A, Schuler M, Yoshino T, Delord JP, Yamada Y, Lolkema MP, Faris JE, Eskens FALM, Sharma S, Yaeger R, Lenz HJ, Wainberg ZA, Avsar E, Chatterjee A, Jaeger S, Tan E, Maharry K, Demuth T, Schellens JHM (2017) A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov 7:610–619. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O’Neil BH, Atkins JN, Berry S, Polite BN, O’Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB, Mulkerin DL, Mayer RJ, Blanke C (2017) Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer. Jama 317:2392. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Welsch ME, Kaplan A, Chambers JM, Stokes ME, Bos PH, Zask A, Zhang Y, Sanchez-Martin M, Badgley MA, Huang CS, Tran TH, Akkiraju H, Brown LM, Nandakumar R, Cremers S, Yang WS, Tong L, Olive KP, Ferrando A, Stockwell BR (2017) Multivalent small-molecule pan-RAS inhibitors. Cell 168:878–889.e29. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Wieduwilt M, Moasser M (2008) The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci 65:1566–1584. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 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
  104. Yang X, Zhang X, Mortenson ED, Radkevich-Brown O, Wang Y, Fu YX (2013a) Cetuximab-mediated tumor regression depends on innate and adaptive immune responses. Mol Ther 21:91–100. CrossRefPubMedGoogle Scholar
  105. Yang Z-Y, Wu X-Y, Huang Y-F, Di M-Y, Zheng D-Y, Chen J-Z, Ding H, Mao C, Tang J-L (2013b) Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a systematic review with meta-analysis. Int J Cancer 133:1914–1925. CrossRefPubMedGoogle Scholar
  106. Yar Saglam AS, Alp E, Elmazoglu Z, Menevse S (2015) Treatment with cucurbitacin B alone and in combination with gefitinib induces cell cycle inhibition and apoptosis via EGFR and JAK/STAT pathway in human colorectal cancer cell lines. Hum Exp Toxicol 35:526–543. CrossRefPubMedGoogle Scholar
  107. Yoon J, Koo KH, Choi KY (2011) MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 71:445–453. CrossRefPubMedGoogle Scholar
  108. Zhao L, Vogt PK (2008) Helical domain and kinase domain mutations in p110 of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105:2652–2657. CrossRefPubMedGoogle Scholar
  109. Zhao L, Vogt PK (2010) Hot-spot mutations in p110α of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle 9:596–600. CrossRefPubMedPubMedCentralGoogle Scholar
  110. Ziemke EK, Dosch JS, Maust JD, Shettigar A, Sen A, Welling TH, Hardiman KM, Sebolt-Leopold JS (2016) Sensitivity of KRAS-mutant colorectal cancers to combination therapy that cotargets MEK and CDK4/6. Clin Cancer Res 22:405–414. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Marta Martins
    • 1
    Email author
  • André Mansinho
    • 2
  • Raquel Cruz-Duarte
    • 1
  • Soraia Lobo Martins
    • 2
  • Luís Costa
    • 1
    • 2
  1. 1.Instituto de Medicina Molecular – João Lobo Antunes, Faculty of MedicineUniversity of LisbonLisbonPortugal
  2. 2.Oncology Division, Santa Maria HospitalCentro Hospitalar Lisboa NorteLisbonPortugal

Personalised recommendations