Skip to main content

Advertisement

SpringerLink
Log in

Combining trastuzumab and cetuximab combats trastuzumab-resistant gastric cancer by effective inhibition of EGFR/ErbB2 heterodimerization and signaling

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The anti-ErbB2 antibody trastuzumab has currently been approved for ErbB2-positive gastric cancer. Despite the effectiveness of trastuzumab, resistance is common. Thus, there is an urgent need to overcome trastuzumab resistance. Here, we obtain a trastuzumab-resistant cell line, which is derived from the human gastric cancer NCI-N87 cell line, by modeling the development of acquired resistance in patients. Our data show that combining trastuzumab and cetuximab leads to a significant decrease in EGFR/ErbB2 heterodimers and signaling compared with either antibody alone, and the combination results in greater antitumor activity against the trastuzumab-resistant NCI-N87 cell line, both in vitro and in vivo, suggesting that a combined EGFR/ErbB2 inhibition may overcome trastuzumab resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ (2009) Gastric cancer. Lancet 374:477–490

    Article  PubMed  Google Scholar 

  2. Hofmann M, Stoss O, Shi D, Büttner R, van de Vijver M, Kim W, Ochiai A, Rüschoff J, Henkel T (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52:797–805

    Article  CAS  PubMed  Google Scholar 

  3. Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, Soini Y, Helin H, Salo J, Joensuu H, Sihvo E, Elenius K, Isola J (2005) Amplification of HER-2 in gastric carcinoma: association with topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 16:273–278

    Article  CAS  PubMed  Google Scholar 

  4. Matsubara J, Yamada Y, Nakajima TE, Kato K, Hamaguchi T, Shirao K, Shimada Y, Shimoda T (2008) Clinical significance of insulin-like growth factor type 1 receptor and epidermal growth factor receptor in patients with advanced gastric cancer. Oncology 74:76–83

    Article  CAS  PubMed  Google Scholar 

  5. Hudis CA (2007) Trastuzumab: mechanism of action and use in clinical practice. N Engl J Med 357:39–51

    Article  CAS  PubMed  Google Scholar 

  6. Nahta R, Esteva FJ (2006) HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res 8:215

    Article  PubMed Central  PubMed  Google Scholar 

  7. Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ (2009) Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res 69:2191–2194

    Article  CAS  PubMed  Google Scholar 

  8. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C, Chin L, DePinho RA (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290

    Article  CAS  PubMed  Google Scholar 

  9. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D (2011) Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 17:461–469

    Article  PubMed  Google Scholar 

  10. Mendelsohn J (2002) Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20:1S–13S

    CAS  PubMed  Google Scholar 

  11. Schmitz KR, Ferguson KM (2009) Interaction of antibodies with ErbB receptor extracellular regions. Exp Cell Res 315:659–670

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Patel D, Bassi R, Hooper A, Prewett M, Hicklin DJ, Kang X (2009) Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. Int J Oncol 34:25–32

    CAS  PubMed  Google Scholar 

  13. Kondo N, Tsukuda M, Sakakibara A, Takahashi H, Hyakusoku H, Komatsu M, Niho T, Nakazaki K, Toth G (2012) Combined molecular targeted drug therapy for EGFR and HER-2 in head and neck squamous cell carcinoma cell lines. Int J Oncol 40:1805–1812

    CAS  PubMed  Google Scholar 

  14. Larbouret C, Gaborit N, Chardès T, Coelho M, Campigna E, Bascoul-Mollevi C, Mach JP, Azria D, Robert B, Pèlegrin A (2012) In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatmentwith trastuzumab/erlotinib or lapatinib alone implication of receptors’ down-regulation and dimers’ disruption. Neoplasia 14:121–130

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3 K complex is disrupted by trastuzumab and is effectively inhibited by thePI3 K inhibitor GDC-0941. Cancer Cell 15:429–440

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Bohua Li for critical comments on the manuscript. This work was supported by the Hebei Medical science research program (20130345) from the Health Department of Hebei Province, and the technology support program (201202) from Harrison International Peace Hospital. The authors thank Ms. Yanchun Meng and Mr. Shi Hu for their technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Central Laboratory, Harrison International Peace Hospital, 180 Ren Min East Road, Hengshui, 053000, Hebei, People’s Republic of China

    Lei Zheng, Wenlong Tan, Jinrong Zhang & Hongmei Liu

  2. State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People’s Republic of China

    Lei Zheng

  3. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Wenlong Tan

  4. Department of Neurology, Harrison International Peace Hospital, Hengshui, People’s Republic of China

    Dongcai Yuan

  5. Department of Hematology, The Second Hospital, Hebei Medical University, Shijiazhuang, People’s Republic of China

    Jingci Yang

Authors
  1. Lei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenlong Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinrong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongcai Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingci Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongmei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lei Zheng or Hongmei Liu.

Additional information

Lei Zheng, Wenlong Tan and Jinrong Zhang have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zheng, L., Tan, W., Zhang, J. et al. Combining trastuzumab and cetuximab combats trastuzumab-resistant gastric cancer by effective inhibition of EGFR/ErbB2 heterodimerization and signaling. Cancer Immunol Immunother 63, 581–586 (2014). https://doi.org/10.1007/s00262-014-1541-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1541-z

Keywords

Search

Navigation