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Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models

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Abstract

Erlotinib (Tarceva®, OSI-774) is a potent, orally available, small-molecule inhibitor of HER1/EGFR tyrosine-kinase activity. In this study, the antitumor activity of erlotinib was evaluated in two human colorectal tumor xenograft models (LoVo and HCT116) in athymic mice. When erlotinib was administered as monotherapy, significant tumor growth inhibition (TGI) was seen in the LoVo model at both 100 mg/kg [TGI > 100%, P < 0.001; 6/10 partial regressions (PRs)] and 25 mg/kg (TGI = 79%, P < 0.001) doses. However, the HCT116 xenograft model was not responsive to any dose of erlotinib tested. The differential response to erlotinib of these two tumor models was not a result of differences in HER1/EGFR expression levels since these were similar in both cell lines. However, it was demonstrated that resistance to erlotinib in the HCT116 model may be a result of persistent activation of ERK in these tumors. Based on the single agent activity of erlotinib in LoVo tumors, a combination study with CPT-11 (Camptosar®, irinotecan) was performed. CPT-11 at the optimal dose of 60 mg/kg or a lower dose of 15 mg/kg resulted in significant TGI (TGI > 100%, P < 0.001, and TGI = 93%, P < 0.001, respectively) in LoVo-bearing mice. Combination treatment with erlotinib (25 mg/kg) and CPT-11 (15 mg/kg) produced significantly greater antitumor activity (TGI > 100%, P < 0.001; 10/10 PRs) than either agent alone (P < 0.05), with no increase in toxicity. These data indicate that erlotinib can enhance the antitumor activity of CPT-11, without enhanced toxicity, in the LoVo human colorectal tumor xenograft model.

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References

  1. Aggarwal S, Chu E (2005) Current therapies for advanced colorectal cancer. Oncology (Williston Park) 19:589–595

    Google Scholar 

  2. Albanell J, Codony-Servat J, Rojo F, Del Campo JM, Sauleda S, Anido J, Raspall G, Giralt J, Rosello J, Nicholson RI, Mendelsohn J, Baselga J (2001) Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor-α expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. Cancer Res 61:6500–6510

    PubMed  CAS  Google Scholar 

  3. Arteaga CL (2002) Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 7(Suppl 4):31–39

    Article  PubMed  CAS  Google Scholar 

  4. Barber TD, Vogelstein B, Kinzler KW, Velculescu VE (2004) Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351:2883

    Article  PubMed  CAS  Google Scholar 

  5. Grunwald V, Hidlago M (2003) Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 95:871–967

    Google Scholar 

  6. Herbst RS (2004) Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 59(2 Suppl):21–26

    Article  PubMed  CAS  Google Scholar 

  7. Hidalgo M, Bloedow D (2003) Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of Erlotinib (Tarceva). Semin Oncol 30:25–33

    PubMed  CAS  Google Scholar 

  8. Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L, Ferrante K, Von Hoff DD, Silberman S, Rowinsky EK (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279

    PubMed  CAS  Google Scholar 

  9. Higgins B, Kolinsky K, Smith M, Beck G, Rashed M, Adames V, Linn M, Wheeldon E, Gand L, Birnboeck H, Hoffmann G (2004) Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. Anticancer Drugs 15(5):503–512

    Article  PubMed  CAS  Google Scholar 

  10. Janmaat ML, Kruyt FA, Rodriguez JA, Giaccone G (2003) Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9(6):2316–2326

    PubMed  CAS  Google Scholar 

  11. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130

    Article  PubMed  Google Scholar 

  12. Kamai T, Takagi K, Asami H, Ito Y, Arai K, Yoshida KI (2000) Prognostic significance of p27Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int 86:14–19

    Article  PubMed  CAS  Google Scholar 

  13. Khamly K, Jefford M, Micheal M, Zalcberg J (2005) Beyond 5-fluorouracil: new horizons in systemic therapy for advanced colorectal cancer. Expert Opin Investig Drugs 14(6):607–624

    Article  PubMed  CAS  Google Scholar 

  14. Lavelle F, Bissery MC, Andre S, Roquet F, Riou JF (1996) Preclinical evaluation of CPT-11 and its active metabolite SN38. Semin Oncol 23:11–20

    PubMed  CAS  Google Scholar 

  15. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  16. Magne N, Fischel JL, Dubreuil A, Formento P, Poupon MF, Laurent-Puig P, Milano G (2002) Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumor cells on the antiproliferative effect of ZD1839 (“Iressa”). Br J Cancer 86:1518–1523

    Article  PubMed  CAS  Google Scholar 

  17. Malik SN, Siu LL, Rowinsky EK, deGraffenried L, Hammond LA, Rizzo J, Bacus S, Brattain MG, Kreisberg JI, Hidalgo M (2003) Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin Cancer Res 9:2478–2486

    PubMed  CAS  Google Scholar 

  18. 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(8):2454–2460

    Article  PubMed  CAS  Google Scholar 

  19. Moasser MM, Basso A, Averbuch SD, Rosen N (2001) The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184–7188

    PubMed  CAS  Google Scholar 

  20. Nagahara H, Mimori K, Ohta M, Utsunomiya T, Inoue H, Barnard GF, Ohira M, Hirakawa K, Mori M (2005) Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin Cancer Res 11:1368–1371

    Article  PubMed  CAS  Google Scholar 

  21. Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37(Suppl 4):S9–S15

    Article  PubMed  CAS  Google Scholar 

  22. Pao W, Miller VA (2005) Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 23:2556–2568

    Article  PubMed  CAS  Google Scholar 

  23. Pollack VA, Savage DM, Baker DA, Tsaparikos KE, Sloan DE, Moyer JD, Barbacci EG, Pustilnik LR, Smolarek TA, Davis JA, Vaidya MP, Arnold LD, Doty JL, Iwata KK, Morin MJ (1999) Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291(2):739–748

    PubMed  CAS  Google Scholar 

  24. 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. Tumor Biol 21(2):105–115

    Article  CAS  Google Scholar 

  25. Ranson M (2004) Epidermal growth factor receptor tyrosine kinases inhibitor. Br J Cancer 90:2250–2255

    PubMed  CAS  Google Scholar 

  26. Raymond E, Faivre S, Armand JP (2000) Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 60 (Suppl 1) 5–23, discussion 41–42

  27. Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdu R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DDA (1999) Multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85(4):786–795

    Article  PubMed  CAS  Google Scholar 

  28. Saijo N (2000) Preclinical and clinical trials of topoisomerase inhibitors. Ann N Y Acad Sci 922:92–99

    Article  PubMed  CAS  Google Scholar 

  29. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914

    Article  PubMed  CAS  Google Scholar 

  30. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  31. Soulières D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL (2004) Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22:77–85

    Article  PubMed  CAS  Google Scholar 

  32. Tsao MS, Kamel-Reid S, Shepherd FA (2006) Assessing EGFR mutations. N Engl J Med 354:527–528

    CAS  Google Scholar 

  33. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353:133–144

    Article  PubMed  CAS  Google Scholar 

  34. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2:127–137

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank personnel from the Oncology in vivo section, Hoffmann-La Roche Inc. (Bhupesh Desai, Tom Nevins, Zoran Filipovic, Bernardo Felix, Kathryn Packman, Leopoldo Luistro and Weiguo Qing), and Roche Laboratory Animal Resources (especially Enrique Calderon and David Malcolm). The authors would also like to thank Gardiner-Caldwell Communications.

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Authors and Affiliations

  1. Department of Oncology, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ, 07110, USA

    Jianping Chen, Melissa Smith, Kenneth Kolinsky & Brian Higgins

  2. Department of Safety and Technical Sciences, Hoffmann-La Roche Inc., Nutley, NJ, 07110, USA

    Violeta Adames, Nila Mehta, Luke Fritzky, Mohammad Rashed, Eric Wheeldon & Michael Linn

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  1. Jianping Chen
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  2. Melissa Smith
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Correspondence to Jianping Chen.

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Chen, J., Smith, M., Kolinsky, K. et al. Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models. Cancer Chemother Pharmacol 59, 651–659 (2007). https://doi.org/10.1007/s00280-006-0320-8

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  • DOI: https://doi.org/10.1007/s00280-006-0320-8

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