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The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma

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Abstract

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, exhibit up to a 70% response rate against non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the EGFR gene (EGFR). The mechanism of intrinsic resistance of EGFR mutation-positive NSCLC against EGFR-TKIs is not known. The current study assesses the relationship between the molecular expression of EGFR signals and the response to gefitinib treatment in patients with pulmonary adenocarcinoma to elucidate the mechanism of intrinsic resistance to gefitinib.

Methods

The present study included 30 patients with pulmonary adenocarcinoma who were treated with gefitinib for a postoperative recurrence. The correlation between the response to gefitinib treatment and various clinical and molecular features was evaluated.

Results

EGFR mutations were detected in 20 (66.7%) of the 30 patients. The response to gefitinib treatment was a complete response in 1 case, partial response in 12 cases, stable disease in 4 cases, and progressive disease in 13 cases. Both univariate and multivariate analyses showed the presence of an EGFR mutation, and the expression of phospho-EGFR (p-EGFR) significantly correlated with a better response to gefitinib treatment. Ten of the 16 p-EGFR positive patients were disease controlled, but all 4 p-EGFR negative patients were intrinsically resistant to EGFR-TKIs (P = 0.025). Other factors including sex, smoking status, serum carcinoembryonic antigen and cytokeratin-19 fragment levels, EGFR, Met proto-oncogene, phospho-Met, and hepatocyte growth factor expression were not associated with the response to gefitinib treatment.

Conclusion

These results suggest that, even if EGFR mutations were observed, a p-EGFR negative state might be a cause of intrinsic resistance to EGFR-TKIs.

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References

  1. Iyoda A, Hiroshima K, Moriya Y. Predictors of postoperative survival in patients with locally advanced non-small cell lung carcinoma. Surg Today 2010;40:725–728.

    Article  PubMed  Google Scholar 

  2. Salomon DS, Brandt R, Ciardiello F. Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.

    Article  PubMed  CAS  Google Scholar 

  3. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550–6565.

    Article  PubMed  CAS  Google Scholar 

  4. Selvaggi G, Novello S, Torri V. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004;15:28–32.

    Article  PubMed  CAS  Google Scholar 

  5. Fukuoka M, Yano S, Giaccone G. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237–2246.

    Article  PubMed  CAS  Google Scholar 

  6. Kris MG, Natale RB, Herbst RS. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–2158.

    Article  PubMed  CAS  Google Scholar 

  7. Lynch TJ, Bell DW, Sordella R. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.

    Article  PubMed  CAS  Google Scholar 

  8. Paez JG, Janne PA, Lee JC. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.

    Article  PubMed  CAS  Google Scholar 

  9. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817–1824.

    Article  PubMed  CAS  Google Scholar 

  10. Inoue A, Suzuki T. Prospective phase II study of gefitinib for chemotherapy-naïve patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 2006;24:3340–3346.

    Article  PubMed  CAS  Google Scholar 

  11. Kobayashi S, Boggon TJ, Dayaram T. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.

    Article  PubMed  CAS  Google Scholar 

  12. Pao W, Miller VA, Politi KA. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.

    Article  PubMed  Google Scholar 

  13. Engelman JA, Zejnullahu K, Mitsudomi T. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039–1043.

    Article  PubMed  CAS  Google Scholar 

  14. Bean J, Brennan C, Shih JY. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007;104:20932–20937.

    Article  PubMed  CAS  Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, N ational Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.

    Article  PubMed  CAS  Google Scholar 

  16. Nakamura Y, Niki T, Goto A. c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci 2007;98:1006–1013.

    Article  PubMed  CAS  Google Scholar 

  17. Han SW, Hwang PG, Chung DH. Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa, ZD1939) in chemotherapy-resistant non-small cell cancer. Int J Cancer 2005;113:109–115.

    Article  PubMed  CAS  Google Scholar 

  18. Matsuya D, Huang C, Liu D. The tumor-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumor growth and prognosis in non-smallcell lung cancer patients. Br J Cancer 2004;90:1555–1562.

    Article  Google Scholar 

  19. Hirsch FR, Varella-Garcia M, Bunn PA. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003;21:3798–3807.

    Article  PubMed  CAS  Google Scholar 

  20. Suzuki T, Nakagawa T, Endo H. The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 (“Iressa”) is not related to the expression of EGFR or HER-2 or to K-ras gene status. Lung Cancer 2003;42:35–41.

    Article  PubMed  Google Scholar 

  21. Yano S, Wang W, Li Q, Matsumoto K. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 2008;68:9479–9487.

    Article  PubMed  CAS  Google Scholar 

  22. Wu JY, Wu SG, Yang CH, Gow CH. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 2008;14:4877–4882.

    Article  PubMed  CAS  Google Scholar 

  23. Zang X, Gureasko J, Shen K, Cole PA. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006;125:1137–1149.

    Article  Google Scholar 

  24. Wood ER, Truesdale AT, McDonald OB, Yuan D. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib) relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004;64:6652–6659.

    Article  PubMed  CAS  Google Scholar 

  25. Choi SH, Mendrola JM, Lemmon MA. EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 2007;26:1567–1576.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Daigo Kawano, Tokujiro Yano, Fumihiro Shoji, Kensaku Ito, Yosuke Morodomi, Akira Haro, Naoko Miura, Tomoyoshi Takenaka & Yoshihiko Maehara

  2. Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

    Ichiro Yoshino

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  1. Daigo Kawano
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  2. Tokujiro Yano
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  3. Fumihiro Shoji
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  4. Kensaku Ito
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  5. Yosuke Morodomi
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  9. Ichiro Yoshino
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  10. Yoshihiko Maehara
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Kawano, D., Yano, T., Shoji, F. et al. The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma. Surg Today 41, 818–823 (2011). https://doi.org/10.1007/s00595-011-4514-2

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  • DOI: https://doi.org/10.1007/s00595-011-4514-2

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