Pharmacologic resistance in colorectal cancer: A review

Therapeutic Advances in Medical Oncology

Volumn 8, Issue 1, 2016, Pages 57-84

  Hammond, William A ^a   Swaika, Abhisek ^a   Mody, Kabir ^b  

^a MAYO CLINIC   (United States)

^b MAYO CLINIC   (United States)

Author keywords

Colon adenocarcinoma; Colon cancer; Resistance

Indexed keywords

AFLIBERCEPT; BEVACIZUMAB; CAPECITABINE; CYTOSTATIC AGENT; FIRTECAN; FLUOROURACIL; GIMERACIL PLUS OTERACIL POTASSIUM PLUS TEGAFUR; IRINOTECAN; OXALIPLATIN; PANITUMUMAB; RAMUCIRUMAB; REGORAFENIB; TEGAFUR;

APOPTOSIS; CANCER CHEMOTHERAPY; CANCER RESISTANCE; CANCER STAGING; COLORECTAL CANCER; DOWN REGULATION; DRUG EFFICACY; GENE EXPRESSION; GENETIC VARIABILITY; HEREDITARY NONPOLYPOSIS COLORECTAL CANCER; HUMAN; IMMUNOHISTOCHEMISTRY; META ANALYSIS; MOLECULARLY TARGETED THERAPY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMATIC REVIEW; TREATMENT RESPONSE; UPREGULATION;

EID: 84951827874     PISSN: 17588340     EISSN: 17588359     Source Type: Journal    
DOI: 10.1177/1758834015614530     Document Type: Review

References (191)

1. Abdalla E. Vauthey J. Ellis L. Ellis V. Pollock R. Broglio K. et al. (2004) Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection / ablation for colorectal liver metastases. Ann Surg 239: 818–825; discussion 825–827.
2. Adam R. Delvart V. Pascal G. Valeanu A. Castaing D. Azoulay D. et al. (2004) Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 240: 644–657; discussion 657–658.
3. Allegra C. Jessup J. Somerfield M. Hamilton S. Hammond E. Hayes D. et al. (2009) American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27: 2091–2096.
4. Amado R. Wolf M. Peeters M. van Cutsem E. Siena S. Freeman D. et al. (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26: 1626–34.
5. Baba H. Watanabe M. Okabe H. Miyamoto Y. Sakamoto Y. Baba Y. et al. (2012) Upregulation of ERCC 1 and DPD expressions after oxaliplatin-based first-line chemotherapy for metastatic colorectal cancer. Br J Cancer 107: 1950–1955.
6. Barber T. Vogelstein B. Kinzler K. Velculescu V. (2004) Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351: 2883.
7. Bardelli A. Corso S. Bertotti A. Hobor S. Valtorta E. Siravegna G. et al. (2013) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3: 658–673.
8. Bardelli A. Siena S. (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28: 1254–1261.
9. Batchelor T. Sorensen A. Di Tomaso E. Zhang W. Duda D. Cohen K. et al. (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11: 83–95.
10. Becouarn Y. Ychou M. Ducreux M. Borel C. Bertheault-Cvitkovic F. Seitz J. et al. (1998) Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 16: 2739–2744.
11. Bennouna J. Sastre J. Arnold D. Osterlund P. Greil R. van Cutsem E. et al. (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14: 29–37.
12. Berger S. Jenh C. Johnson L. Berger F. (1985) Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol Pharmacol 28: 461–467.
13. Bergers G. Hanahan D. (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8: 592–603.
14. Bertotti A. Migliardi G. Galimi F. Sassi F. Torti D. Isella C. et al. (2011) A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER 2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1: 508–523.
15. Boyer J. Mclean E. Aroori S. Wilson P. Mcculla A. Carey P. et al. (2004) Characterization of p 53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. Clin Cancer Res 10: 2158–2167.
16. Cao C. Zhang X. Kuang M. Gu D. He M. Chen J. et al. (2014) Survival benefit from S-1 as compared to Fluorouracil in Asian patients with advanced gastrointestinal cancer: a meta-analysis. Cancer Sci 105: 1008–1014.
17. Cappuzzo F. Finocchiaro G. Rossi E. Janne P. Carnaghi C. Calandri C. et al. (2008) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19: 717–723.
18. Care thers J. Smith E. Behling C. Nguyen L. Tajima A. Doctolero R. et al. (2004) Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 126: 394–401.
19. Carlini L. Meropol N. Bever J. Andria M. Hill T. Gold P. et al. (2005) UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 11: 1226–1236.
20. Casanovas O. Hicklin D. Bergers G. Hanahan D. (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8: 299–309.
21. Cassidy J. Saltz L. Twelves C. van Cutsem E. Hoff P. Kang Y. et al. (2011) Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann Oncol 22: 2604–2609.
22. Choi Y. Kim T. Kim K. Lee S. Hong Y. Ryu M. et al. (2012) A Phase II study of clinical outcomes of 3-week cycles of irinotecan and S-1 in patients with previously untreated metastatic colorectal cancer: influence of the UGT1A1 and CYP2A6 polymorphisms on clinical activity. Oncology 82: 290–297.
23. Chu E. Koeller D. Johnston P. Zinn S. Allegra C. (1993) Regulation of thymidylate synthase in human colon cancer cells treated with 5-fluorouracil and interferon-gamma. Mol Pharmacol 43: 527–533.
24. Ciardiello F. Bianco R. Damiano V. Fontanini G. Caputo R. Pomatico G. et al. (2000) Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C 225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6: 3739–3747.
25. Ciardiello F. Normanno N. (2011) HER2 signaling and resistance to the anti-EGFR monoclonal antibody cetuximab: a further step toward personalized medicine for patients with colorectal cancer. Cancer Discov 1: 472–474.
26. Ciardiello F. Tortora G. (2008) EGFR antagonists in cancer treatment. N Engl J Med 358: 1160–1174.
27. Colucci G. Gebbia V. Paoletti G. Giuliani F. Caruso M. Gebbia N. et al. (2005) Phase III randomized trial of FOLFIRI versus FOLFOX 4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23: 4866–4875.
28. Crawford Y. Kasman I. Yu L. Zhong C. Wu X. Modrusan Z. et al. (2009) PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15: 21–34.
29. Cubillo A. Rodriguez-Pascual J. Lopez-Rios F. Plaza C. Garcia E. Alvarez R. et al. (2014) Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal cancer. Am J Clin Oncol.
30. Cummings J. Boyd G. Ethell B. Macpherson J. Burchell B. Smyth J. et al. (2002) Enhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation. Biochem Pharmacol 63: 607–613.
31. Cunningham D. Humblet Y. Siena S. Khayat D. Bleiberg H. Santoro A. et al. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351: 337–345.
32. Cunningham D. Pyrhonen S. James R. Punt C. Hickish T. Heikkila R. et al. (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352: 1413–1418.
33. de Gramont A. Figer A. Seymour M. Homerin M. Hmissi A. Cassidy J. et al. (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947.
34. de Palma M. Venneri M. Galli R. Sergi L. Politi L. Sampaolesi M. et al. (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8: 211–226.
35. de Roock W. Claes B. Bernasconi D. de Schutter J. Biesmans B. Fountzilas G. et al. (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: 753–762.
36. de Stefano A. Carlomagno C. (2014) Beyond KRAS: Predictive factors of the efficacy of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer. World J Gastroenterol 20: 9732–9743.
37. Di Nicolantonio F. Martini M. Molinari F. Sartore-Bianchi A. Arena S. Saletti P. de Dosso S. et al. (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26: 5705–5712.
38. Diaz-Rubio E. Sastre J. Zaniboni A. Labianca R. Cortes-Funes H. de Braud F. et al. (1998) Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol 9: 105–108.
39. Douillard J. Cunningham D. Roth A. Navarro M. James R. Karasek P. et al. (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355: 1041–1047.
40. Douillard J. Oliner K. Siena S. Tabernero J. Burkes R. Barugel M. et al. (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369: 1023–1034.
41. Douillard J. Siena S. Cassidy J. Tabernero J. Burkes R. Barugel M. et al. (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX 4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28: 4697–4705.
42. Du R. Lu K. Petritsch C. Liu P. Ganss R. Passegue E. et al. (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13: 206–220.
43. Esposito C. Rachiglio A. La Porta M. Sacco A. Roma C. Iannaccone A. et al. (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: 1143–1146.
44. Etienne-Grimaldi M. Milano G. Maindrault-Goebel F. Chibaudel B. Formento J. Francoual M. et al. (2010) Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients. Br J Clin Pharmacol 69: 58–66.
45. Fedier A. Steiner R. Schwarz V. Lenherr L. Haller U. Fink D. (2003) The effect of loss of Brca 1 on the sensitivity to anticancer agents in p53-deficient cells. Int J Oncol 22: 1169–1173.
46. Feng J. Tamaskovic R. Yang Z. Brazil D. Merlo A. Hess D. et al. (2004) Stabilization of Mdm 2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem 279: 35510–35517.
47. Fink D. Aebi S. Howell S. (1998) The role of DNA mismatch repair in drug resistance. Clin Cancer Res 4: 1–6.
48. Fink D. Zheng H. Nebel S. Norris P. Aebi S. Lin T. et al. (1997) In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer research 57: 1841–1845.
49. Frattini M. Saletti P. Romagnani E. Martin V. Molinari F. Ghisletta M. et al. (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97: 1139–1145.
50. Fujiwara Y. Minami H. (2010) An overview of the recent progress in irinotecan pharmacogenetics. Pharmacogenomics 11: 391–406.
51. Giacchetti S. Perpoint B. Zidani R. Le Bail N. Faggiuolo R. Focan C. et al. (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18: 136–147.
52. Gongora C. Vezzio-Vie N. Tuduri S. Denis V. Causse A. Auzanneau C. et al. (2011) New Topoisomerase I mutations are associated with resistance to campto thecin. Molecular Cancer 10: 64.
53. Gottesman M. Fojo T. Bates S. (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2: 48–58.
54. Grothey A. van Cutsem E. Sobrero A. Siena S. Falcone A. Ychou M. et al. (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381: 303–312.
55. Hattori K. Heissig B. Wu Y. Dias S. Tejada R. Ferris B. et al. (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8: 841–849.
56. Hector S. Bolanowska-Higdon W. Zdanowicz J. Hitt S. Pendyala L. (2001) In vitro studies on the mechanisms of oxaliplatin resistance. Cancer Chemother Pharmacol 48: 398–406.
57. Heidelberger C. Chaudhuri N. Danneberg P. Mooren D. Griesbach L. Duschinsky R. et al. (1957) Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179: 663–666.
58. Hirschi B. Gallmeier E. Ziesch A. Marschall M. Kolligs F. (2014) Genetic targeting of B-RafV600E affects survival and proliferation and identifies selective agents against BRAF-mutant colorectal cancer cells. Mol Cancer 13: 122.
59. Hobor S. van Emburgh B. Crowley E. Misale S. Di Nicolantonio F. Bardelli A. (2014) TGF-alpha and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells. Clin Cancer Res 20: 6429–6438.
60. Hoff P. Ansari R. Batist G. Cox J. Kocha W. Kuperminc M. et al. (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19: 2282–2292.
61. Hohla F. Winder T. Greil R. Rick F. Block N. Schally A. (2014) Targeted therapy in advanced metastatic colorectal cancer: current concepts and perspectives. World J Gastroenterol 20: 6102–6112.
62. Holzer A. Manorek G. Howell S. (2006) Contribution of the major copper influx transporter CTR 1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin. Mol Pharmacol 70: 1390–1394.
63. Hong Y. Park Y. Lim H. Lee J. Kim T. Kim K. et al. (2012) S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol 13: 1125–1132.
64. Houghton J. Houghton P. (1983) Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma. Eur J Cancer Clin Oncol 19: 807–815.
65. Hudis C. (2007) Trastuzumab - mechanism of action and use in clinical practice. N Engl J Med 357: 39–51.
66. Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342.
67. Ishikawa T. Ali-Osman F. (1993) Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 268: 20116–20125.
68. Isshi K. Sakuyama T. Gen T. Nakamura Y. Kuroda T. Katuyama T. et al. (2002) Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU. Int J Clin Oncol 7: 335–342.
69. Jhawer M. Goel S. Wilson A. Montagna C. Ling Y. Byun D. et al. (2008) PIK3CA mutation / PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68: 1953–1961.
70. Johnston P. Lenz H. Leichman C. Danenberg K. Allegra C. Danenberg P. et al. (1995) Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 55: 1407–1412.
71. Jonker D. O'Callaghan C. Karapetis C. Zalcberg J. Tu D. Au H. et al. (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357: 2040–2048.
72. Jurgensmeier J. Schmoll H. Robertson J. Brooks L. Taboada M. Morgan S. et al. (2013) Prognostic and predictive value of VEGF, SVEGFR-2 and CEA in mCRC studies comparing cediranib, bevacizumab and chemotherapy. Br J Cancer 108: 1316–1323.
73. Kamba T. McDonald D. (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96: 1788–1795.
74. Karapetis C. Khambata-Ford S. Jonker D. O'Callaghan C. Tu D. Tebbutt N. et al. (2008) K-Ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359: 1757–1765.
75. Kelland L. (1993) New platinum antitumor complexes. Crit Rev Oncol Hematol 15: 191–219.
76. Kim K. Li B. Winer J. Armanini M. Gillett N. Phillips H. et al. (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362: 841–844.
77. Kim S. Hong S. Shim K. Kong S. Shin A. Baek J. et al. (2013) S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis. Br J Cancer 109: 1420–1427.
78. Kojima A. Hackett N. Crystal R. (1998) Reversal of CPT-11 resistance of lung cancer cells by adenovirus-mediated gene transfer of the human carboxylesterase cDNA. Cancer Res 58: 4368–4374.
79. Koopman M. Venderbosch S. van Tinteren H. Ligtenberg M. Nagtegaal I. van Krieken J. et al. (2009) Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study. Eur J Cancer 45: 1999–2006.
80. Kopetz S. Hoff P. Morris J. Wolff R. Eng C. Glover K. et al. (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28: 453–459.
81. Leichman C. Fleming T. Muggia F. Tangen C. Ardalan B. Doroshow J. et al. (1995) Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 13: 1303–1311.
82. Leichman C. Lenz H. Leichman L. Danenberg K. Baranda J. Groshen S. et al. (1997) Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 15: 3223–3229.
83. Li D. Xie K. Ding G. Li J. Chen K. Li H. et al. (2014) Tumor resistance to anti-VEGF therapy through up-regulation of VEGF-C expression. Cancer Lett 346: 45–52.
84. Liang J. Jiang T. Yao R. Liu Z. Lv H. Qi W. (2010) The combination of ERCC 1 and XRCC 1 gene polymorphisms better predicts clinical outcome to oxaliplatin-based chemotherapy in metastatic colorectal cancer. Cancer Chemother Pharmacol 66: 493–500.
85. Lieu C. Tran H. Jiang Z. Mao M. Overman M. Lin E. et al. (2013) The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PloS ONE 8: e77117.
86. Lievre A. Bachet J. Le Corre D. Boige V. Landi B. Emile J. et al. (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66: 3992–3995.
87. Lindskog E. Derwinger K. Gustavsson B. Falk P. Wettergren Y. (2014) Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer. BMC Clin Pathol 14: 25.
88. Longley D. Boyer J. Allen W. Latif T. Ferguson P. Maxwell P. et al. (2002) The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates. Cancer Res 62: 2644–2649.
89. Longley D. Harkin D. Johnston P. (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3: 330–338.
90. Longley D. Johnston P. (2005) Molecular mechanisms of drug resistance. J Pathol 205: 275–292.
91. Lowenstein E. Daly R. Batzer A. Li W. Margolis B. Lammers R. et al. (1992) The SH 2 and SH 3 domain-containing protein GRB 2 links receptor tyrosine kinases to Ras signaling. Cell 70: 431–442.
92. Mancuso M. Davis R. Norberg S. O'Brien S. Sennino B. Nakahara T. et al. (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116: 2610–2621.
93. Marcuello E. Altes A. Menoyo A. Del Rio E. Gomez-Pardo M. Baiget M. 2004. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 91: 678–682.
94. Marcuello E. Altes A. Menoyo A. Rio E. Baiget M. (2006) Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 57: 835–840.
95. Maxwell P. Dachs G. Gleadle J. Nicholls L. Harris A. Stratford I. et al. (1997) Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A 94: 8104–8109.
96. Mayer A. Takimoto M. Fritz E. Schellander G. Kofler K. Ludwig H. (1993) The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and MDR gene expression in colorectal cancer. Cancer 71: 2454–2460.
97. Mayer R. van Cutsem E. Falcone A. Yoshino T. Garcia-Carbonero R. Mizunuma N. et al. (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372: 1909–1919.
98. McLeod H. Keith W. (1996) Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity. Br J Cancer 74: 508–512.
99. Meijer C. Mulder N. Timmer-Bosscha H. Sluiter W. Meersma G. de Vries E. (1992) Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. Cancer Res 52: 6885–6889.
100. Meriggi F. Vermi W. Bertocchi P. Zaniboni A. (2014) The emerging role of NRAS mutations in colorectal cancer patients selected for anti-EGFR therapies. Rev Recent Clin Trials 9: 8–12.
101. Meropol N. Gold P. Diasio R. Andria M. Dhami M. Godfrey T. et al. (2006) Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 24: 4069–4077.
102. Mesange P. Poindessous V. Sabbah M. Escargueil A. de Gramont A. Larsen A. (2014) Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. Oncotarget 5: 4709–4721.
103. Messa C. Russo F. Caruso M. Di Leo A. (1998) EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 37: 285–289.
104. Meyers M. Wagner M. Hwang H. Kinsella T. Boothman D. (2001) Role of the hMLH 1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res 61: 5193–5201.
105. Misale S. Di Nicolantonio F. Sartore-Bianchi A. Siena S. Bardelli A. (2014) Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov 4: 1269–1280.
106. Misale S. Yaeger R. Hobor S. Scala E. Janakiraman M. Liska D. et al. (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486: 532–536.
107. Mitchell E. (2013) Targeted therapy for metastatic colorectal cancer: role of aflibercept. Clin Colorectal Cancer 12: 73–85.
108. Mizukami Y. Jo W. Duerr E. Gala M. Li J. Zhang X. et al. (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nature Med 11: 992–997.
109. Moertel C. Fleming T. Macdonald J. Haller D. Laurie J. Goodman P. et al. (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322: 352–358.
110. Moroni M. Veronese S. Benvenuti S. Marrapese G. Sartore-Bianchi A. Di Nicolantonio F. et al. (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.
111. Moutinho C. Martinez-Cardus A. Santos C. Navarro-Perez V. Martinez-Balibrea E. Musulen E. et al. (2014) Epigenetic inactivation of the BRCA 1 interactor SRBC and resistance to oxaliplatin in colorectal cancer. J Natl Cancer Inst 106: djt322.
112. Muhale F. Wetmore B. Thomas R. McLeod H. (2011) Systems pharmacology assessment of the 5-fluorouracil pathway. Pharmacogenomics 12: 341–350.
113. Muro K. Boku N. Shimada Y. Tsuji A. Sameshima S. Baba H. et al. (2010) Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2 / 3 non-inferiority study (FIRIS study). Lancet Oncol 11: 853–860.
114. Nicum S. Midgley R. Kerr D. (2000) Chemotherapy for colorectal cancer. J R Soc Med 93: 416–419.
115. Nygard S. Christensen I. Nielsen S. Nielsen H. Brunner N. Spindler K. (2014) Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer. Scand J Gastroenterol 49: 84–91.
116. Paez J. Janne P. Lee J. Tracy S. Greulich H. Gabriel S. et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.
117. Pan Q. Chanthery Y. Liang W. Stawicki S. Mak J. Rathore N. et al. (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11: 53–67.
118. Panczyk M. (2014) Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol 20: 9775–9827.
119. Perrone F. Lampis A. Orsenigo M. Di Bartolomeo M. Gevorgyan A. Losa M. et al. (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 20: 84–90.
120. Petrioli R. Bargagli G. Lazzi S. Pascucci A. Francini E. Bellan C. et al. (2010) Thymidine phosphorylase expression in metastatic sites is predictive for response in patients with colorectal cancer treated with continuous oral capecitabine and biweekly oxaliplatin. Anticancer Drugs 21: 313–319.
121. Pollard J. (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4: 71–78.
122. Popat S. Matakidou A. Houlston R. (2004) Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 22: 529–536.
123. Porebska I. Harlozinska A. Bojarowski T. (2000) Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 21: 105–115.
124. Price T. Newhall K. Peeters M. Kim T. Li J. Cascinu S. et al. (2015) Prevalence and outcomes of patients (pts) with EGFR S492R ectodomain mutations in ASPECCT: Panitumumab (PMAB) vs. cetuximab (CMAB) in pts with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). J Clin Oncol (Suppl. 3): abstr 740.
125. Price T. Peeters M. Kim T. Li J. Cascinu S. Ruff P. et al. (2014) Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 15: 569–579.
126. Qiu L. Tang Q. Bai J. Qian X. Li R. Liu B. et al. (2008) Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: evidence from 24 studies. Int J Cancer 123: 2384–2389.
127. Rajput A. Koterba A. Kreisberg J. Foster J. Willson J. Brattain M. (2007) A novel mechanism of resistance to epidermal growth factor receptor antagonism in vivo. Cancer Res 67: 665–673.
128. Raymond E. Faivre S. Chaney S. Woynarowski J. Cvitkovic E. (2002) Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 1: 227–235.
129. Ribatti D. (2008) The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis 11: 215–221.
130. Ridgway J. Zhang G. Wu Y. Stawicki S. Liang W. Chanthery Y. et al. (2006) Inhibition of Dll 4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444: 1083–1087.
131. Roskoski R. Jr. (2012) ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66: 105–143.
132. Roskoski R. Jr. (2014) The ErbB / HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79: 34–74.
133. Rougier P. van Cutsem E. Bajetta E. Niederle N. Possinger K. Labianca R. et al. (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352: 1407–1412.
134. Rouits E. Boisdron-Celle M. Dumont A. Guerin O. Morel A. Gamelin E. (2004) Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 10: 5151–5159.
135. Rubenstein J. Kim J. Ozawa T. Zhang M. Westphal M. Deen D. et al. (2000) Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2: 306–314.
136. Sakuramoto S. Sasako M. Yamaguchi T. Kinoshita T. Fujii M. Nashimoto A. et al. (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357: 1810–1820.
137. Salomon D. Brandt R. Ciardiello F. Normanno N. (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19: 183–232.
138. Salonga D. Danenberg K. Johnson M. Metzger R. Groshen S. Tsao-Wei D. et al. (2000) Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6: 1322–1327.
139. Saltz L. Clarke S. Diaz-Rubio E. Scheithauer W. Figer A. Wong R. et al. (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26: 2013–2019.
140. Saltz L. Cox J. Blanke C. Rosen L. Fehrenbacher L. Moore M. et al. (2000 a) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343: 905–914.
141. Saltz L. Cox J. Blanke C. Rosen L. Fehrenbacher L. Moore M. et al. (2000 b) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343: 905–914.
142. Samuel S. Fan F. Dang L. Xia L. Gaur P. Ellis L. (2011) Intracrine vascular endothelial growth factor signaling in survival and chemoresistance of human colorectal cancer cells. Oncogene 30: 1205–1212.
143. Saridaki Z. Tzardi M. Papadaki C. Sfakianaki M. Pega F. Kalikaki A. et al. (2011) Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in >/= 2 line cetuximab-based therapy of colorectal cancer patients. PloS ONE 6: e15980.
144. Sartore-Bianchi A. Di Nicolantonio F. Nichelatti M. Molinari F. de Dosso S. Saletti P. et al. (2009) Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PloS ONE 4: e7287.
145. Sartore-Bianchi A. Moroni M. Veronese S. Carnaghi C. Bajetta E. Luppi G. et al. (2007) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25: 3238–3245.
146. Schwartz P. Moir R. Hyde C. Turek P. Handschumacher R. (1985) Role of uridine phosphorylase in the anabolism of 5-fluorouracil. Biochem Pharmacol 34: 3585–3589.
147. Shimada Y. Rougier P. Pitot H. (1996) Efficacy of CPT-11 (irinotecan) as a single agent in metastatic colorectal cancer. Eur J Cancer 32A(Suppl. 3): S13–S17.
148. Shirao K. Hoff P. Ohtsu A. Loehrer P. Hyodo I. Wadler S. et al. (2004) Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil / tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV. J Clin Oncol 22: 3466–3474.
149. Shirota Y. Stoehlmacher J. Brabender J. Xiong Y. Uetake H. Danenberg K. et al. (2001) ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 19: 4298–4304.
150. Shojaei F. Wu X. Malik A. Zhong C. Baldwin M. Schanz S. et al. (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25: 911–920.
151. Siegel R. Desantis C. Jemal A. (2014 a) Colorectal cancer statistics, 2014. CA Cancer J Clin 64: 104–117.
152. Siegel R. Ma J. Zou Z. Jemal A. (2014 b) Cancer statistics, 2014. CA Cancer J Clin 64: 9–29.
153. Smith D. Christensen I. Jensen N. Markussen B. Romer M. Nygard S. et al. (2013) Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort. PloS ONE 8: e60613.
154. Sohn K. Croxford R. Yates Z. Lucock M. Kim Y. (2004) Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96: 134–144.
155. Sood A. Mcclain D. Maitra R. Basu-Mallick A. Seetharam R. Kaubisch A. et al. (2012) PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer 11: 143–150.
156. Soong R. Shah N. Salto-Tellez M. Tai B. Soo R. Han H. et al. (2008) Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Ann Oncol 19: 915–919.
157. Spano J. Fagard R. Soria J. Rixe O. Khayat D. Milano G. (2005) Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol 16: 189–194.
158. Stark M. Bram E. Akerman M. Mandel-Gutfreund Y. Assaraf Y. (2011) Heterogeneous nuclear ribonucleoprotein H1/H2-dependent unsplicing of thymidine phosphorylase results in anticancer drug resistance. J Biol Chem 286: 3741–3754.
159. Tabernero J. (2007) The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5: 203–220.
160. Tabernero J. van Cutsem E. Lakomy R. Prausova J. Ruff P. van Hazel G. et al. (2014) Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 50: 320–331.
161. Tabernero J. Yoshino T. Cohn A. Obermannova R. Bodoky G. Garcia-Carbonero R. et al. (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16: 499–508.
162. Takebe N. Zhao S. Ural A. Johnson M. Banerjee D. Diasio R. et al. (2001) Retroviral transduction of human dihydropyrimidine dehydrogenase cDNA confers resistance to 5-fluorouracil in murine hematopoietic progenitor cells and human CD34+-enriched peripheral blood progenitor cells. Cancer Gene Ther 8: 966–973.
163. Tejpar S. Prenen H. Mazzone M. (2012) Overcoming resistance to antiangiogenic therapies. Oncologist 17: 1039–1050.
164. Therkildsen C. Bergmann T. 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 53: 852–864.
165. Thomas H. Coley H. (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10: 159–165.
166. Tokunaga Y. Sasaki H. Saito T. (2007) Clinical role of orotate phosphoribosyl transferase and dihydropyrimidine dehydrogenase in colorectal cancer treated with postoperative fluoropyrimidine. Surgery 141: 346–353.
167. Tournigand C. Andre T. Achille E. Lledo G. Flesh M. Mery-Mignard D. et al. (2004) FOLFIRI followed by FOLFOX 6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22: 229–237.
168. Tsunoda A. Nakao K. Watanabe M. Matsui N. Ooyama A. Kusano M. (2011) Associations of various gene polymorphisms with toxicity in colorectal cancer patients receiving oral uracil and tegafur plus leucovorin: a prospective study. Ann Oncol 22: 355–361.
169. Tsurutani J. Nitta T. Hirashima T. Komiya T. Uejima H. Tada H. et al. (2002) Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan. Lung Cancer 35: 299–304.
170. Vallbohmer D. Kuramochi H. Shimizu D. Danenberg K. Lindebjerg J. Nielsen J. et al. (2006) Molecular factors of 5-fluorouracil metabolism in colorectal cancer: analysis of primary tumor and lymph node metastasis. Int J Oncol 28: 527–533.
171. Vallbohmer D. Yang D. Kuramochi H. Shimizu D. Danenberg K. Lindebjerg J. et al. (2007) DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol 31: 413–418.
172. Vallbohmer D. Zhang W. Gordon M. Yang D. Yun J. Press O. et al. (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23: 3536–3544.
173. van Cutsem E. Labianca R. Bodoky G. Barone C. Aranda E. Nordlinger B. et al. (2009) Randomized phase III trial comparing biweekly infusional fluorouracil / leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 27: 3117–3125.
174. van Cutsem E. Peeters M. Siena S. Humblet Y. Hendlisz A. Neyns B. et al. (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.
175. van Cutsem E. Tabernero J. Lakomy R. Prenen H. Prausova J. Macarulla T. et al. (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 30: 3499–3506.
176. van Cutsem E. Twelves C. Cassidy J. Allman D. Bajetta E. Boyer M. et al. (2001) Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19: 4097–4106.
177. van Emburgh B. Sartore-Bianchi A. Di Nicolantonio F. Siena S. Bardelli A. (2014) Acquired resistance to EGFR-targeted therapies in colorectal cancer. Mol Oncol 8: 1084–1094.
178. Wang H. Bian T. Liu D. Jin T. Chen Y. Lin A. et al. (2011) Association analysis of CYP2A6 genotypes and haplotypes with 5-fluorouracil formation from tegafur in human liver microsomes. Pharmacogenomics 12: 481–492.
179. Wheeler J. Bodmer W. Mortensen N. (2000) DNA mismatch repair genes and colorectal cancer. Gut 47: 148–153.
180. Wilson P. Danenberg P. Johnston P. Lenz H. Ladner R. (2014) Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat Rev Clin Oncol 11: 282–298.
181. Xie H. Wood A. Kim R. Stein C. Wilkinson G. (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5: 243–272.
182. Xu Y. Villalona-Calero M. (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 13: 1841–1851.
183. Yamada K. Araki M. (2001) Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci 114: 2375–2382.
184. Yanagisawa Y. Maruta F. Iinuma N. Ishizone S. Koide N. Nakayama J. et al. (2007) Modified Irinotecan/5FU/Leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes. Scand J Gastroenterol 42: 477–484.
185. Yang L. Debusk L. Fukuda K. Fingleton B. Green-Jarvis B. Shyr Y. et al. (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6: 409–421.
186. Ye D. Zhang J. (2013) Research development of the relationship between thymidine phosphorylase expression and colorectal carcinoma. Cancer Biol Med 10: 10–15.
187. Ye F. Liu Z. Tan A. Liao M. Mo Z. Yang X. (2013) XRCC1 and GSTP1 polymorphisms and prognosis of oxaliplatin-based chemotherapy in colorectal cancer: a meta-analysis. Cancer Chemother Pharmacol 71: 733–740.
188. Yonesaka K. Zejnullahu K. Okamoto I. Satoh T. Cappuzzo F. Souglakos J. et al. (2011) Activation of ERBB 2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 3: 99ra86.
189. Yoshino T. Mizunuma N. Yamazaki K. Nishina T. Komatsu Y. Baba H. et al. (2012) TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 13: 993–1001.
190. Zhang S. Lovejoy K. Shima J. Lagpacan L. Shu Y. Lapuk A. et al. (2006) Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res 66: 8847–8857.
191. Zhao J. Li W. Zhu D. Yu Q. Zhang Z. Sun M. et al. (2014) Association of single nucleotide polymorphisms in MTHFR and ABCG 2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer. Med Oncol 31: 802.