Skip to main content

Advertisement

SpringerLink
Log in

Antitumor activity of a novel EGFR tyrosine kinase inhibitor against human lung carcinoma in vitro and in vivo

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with non-small cell lung cancer (NSCLC). However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the antitumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor (Zhao260054). In vitro studies in a panel of four different human lung cancer cell lines revealed that Zhao260054 inhibited cell proliferation with high potency and induced G0/G1 arrest of cell cycle and apoptosis. Zhao260054 markedly reduced phosphorylation of EGFR and inhibited activation of ERK1/2 and AKT. Oral administration of Zhao260054 (200 mg/kg/day) to BALB/c nude mice bearing SPC-A1 xenografts significantly retarded tumor growth. In conclusion, Zhao260054 has potent antitumor activity on human lung cancer in vitro and in vivo.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. 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 

  2. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98

    Article  PubMed  CAS  Google Scholar 

  3. Yarden Y (2001) The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37(Suppl 4):S3–8

    Article  PubMed  CAS  Google Scholar 

  4. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A (2001) The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 8:11–31

    Article  PubMed  CAS  Google Scholar 

  5. Janne PA, Taffaro ML, Salgia R, Johnson BE (2002) Inhibition of epidermal growth factor receptor signaling in malignant pleural mesothelioma. Cancer Res 62:5242–5247

    PubMed  CAS  Google Scholar 

  6. Mendelsohn J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787–2799

    Article  PubMed  CAS  Google Scholar 

  7. Miller VA, Johnson DH, Krug LM, Pizzo B, Tyson L, Perez W, Krozely P, Sandler A, Carbone D, Heelan RT (2003) Pilot trial of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib plus carboplatin and paclitaxel in patients with stage IIIB or IV non-small-cell lung cancer. J Clin Oncol 21:2094–2100

    Article  PubMed  CAS  Google Scholar 

  8. Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, Krug LM, Pao W, Rizvi N, Pizzo B (2004) Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103–1109

    Article  PubMed  CAS  Google Scholar 

  9. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG (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 

  10. Gridelli C, Maione P, Galetta D, Colantuoni G, Del Gaizo F, Ferrara C, Guerriero C, Nicolella D, Rossi A (2007) Three cases of long-lasting tumor control with erlotinib after progression with gefitinib in advanced non-small cell lung cancer. J Thorac Oncol 2:758–761

    Article  PubMed  Google Scholar 

  11. Choong NW, Dietrich S, Seiwert TY, Tretiakova MS, Nallasura V, Davies GC, Lipkowitz S, Husain AN, Salgia R, Ma PC (2006) Gefitinib response of erlotinib-refractory lung cancer involving meninges—role of EGFR mutation. Nat Clin Pract Oncol 3:50–57

    Article  PubMed  CAS  Google Scholar 

  12. Cho BC, Im CK, Park MS, Kim SK, Chang J, Park JP, Choi HJ, Kim YJ, Shin SJ, Sohn JH (2007) Phase II study of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib. J Clin Oncol 25:2528–2533

    Article  PubMed  CAS  Google Scholar 

  13. Garfield DH (2005) Modern treatment of lung cancer: case 2. Response to erlotinib after failure of gefitinib in a patient with advanced non-small-cell lung carcinoma. J Clin Oncol 23:7738–7740

    Article  PubMed  Google Scholar 

  14. Swaisland HC, Smith RP, Laight A, Kerr DJ, Ranson M, Wilder-Smith CH, Duvauchelle T (2005) Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet 44:1165–1177

    Article  PubMed  CAS  Google Scholar 

  15. Tang PA, Tsao MS, Moore MJ (2006) A review of erlotinib and its clinical use. Expert Opin Pharmacother 7:177–193

    Article  PubMed  CAS  Google Scholar 

  16. Chang JS, Chiang LC, Chen CC, Liu LT, Wang KC, Lin CC (2001) Antileukemic activity of Bidens pilosa L. var. minor (Blume) Sherff and Houttuynia cordata Thunb. Am J Chin Med 29:303–312

    Article  PubMed  CAS  Google Scholar 

  17. Pedro M, Ferreira MM, Cidade H, Kijjoa A, Bronze-da-Rocha E, Nascimento MS (2005) Artelastin is a cytotoxic prenylated flavone that disturbs microtubules and interferes with DNA replication in MCF-7 human breast cancer cells. Life Sci 77:293–311

    Article  PubMed  CAS  Google Scholar 

  18. Okabe T, Okamoto I, Tamura K, Terashima M, Yoshida T, Satoh T, Takada M, Fukuoka M, Nakagawa K (2007) Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res 67:2046–2053

    Article  PubMed  CAS  Google Scholar 

  19. Bai L, Zhu R, Chen Z, Gao L, Zhang X, Wang X, Bai C (2006) Potential role of short hairpin RNA targeting epidermal growth factor receptor in growth and sensitivity to drugs of human lung adenocarcinoma cells. Biochem Pharmacol 71:1265–1271

    Article  PubMed  CAS  Google Scholar 

  20. Zhang M, Zhang X, Bai CX, Song XR, Chen J, Gao L, Hu J, Hong QY, West MJ, Wei MQ (2005) Silencing the epidermal growth factor receptor gene with RNAi may be developed as a potential therapy for non small cell lung cancer. Genet Vaccines Ther 3:5

    Article  PubMed  Google Scholar 

  21. Hara F, Aoe M, Doihara H, Taira N, Shien T, Takahashi H, Yoshitomi S, Tsukuda K, Toyooka S, Ohta T (2005) Antitumor effect of gefitinib (‘Iressa’) on esophageal squamous cell carcinoma cell lines in vitro and in vivo. Cancer Lett 226:37–47

    Article  PubMed  CAS  Google Scholar 

  22. Penne K, Bohlin C, Schneider S, Allen D (2005) Gefitinib (Iressa, ZD1839) and tyrosine kinase inhibitors: the wave of the future in cancer therapy. Cancer Nurs 2005, 28(6):481–486

    Article  Google Scholar 

  23. Madhusudan S, Ganesan TS (2004) Tyrosine kinase inhibitors in cancer therapy. Clin Biochem 37:618–635

    Article  PubMed  CAS  Google Scholar 

  24. Qin B, Ariyama H, Baba E, Tanaka R, Kusaba H, Harada M, Nakano S (2006) Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells. Cancer Chemother Pharmacol 58:577–584

    Article  PubMed  CAS  Google Scholar 

  25. Ariyama H, Qin B, Baba E, Tanaka R, Mitsugi K, Harada M, Nakano S (2006) Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. J Cell Biochem 97:724–734

    Article  PubMed  CAS  Google Scholar 

  26. Bonaccorsi L, Marchiani S, Muratori M, Forti G, Baldi E (2004) Gefitinib (‘IRESSA’, ZD1839) inhibits EGF-induced invasion in prostate cancer cells by suppressing PI3 K/AKT activation. J Cancer Res Clin Oncol 130:604–614

    Article  PubMed  CAS  Google Scholar 

  27. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21:2237–2246

    Article  PubMed  CAS  Google Scholar 

  28. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabarbara P, Bonomi P (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238–3247

    Article  PubMed  CAS  Google Scholar 

  29. Janne PA, Johnson BE (2006) Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res 12:4416s–4420s

    Article  PubMed  Google Scholar 

  30. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8:303–306

    Article  PubMed  CAS  Google Scholar 

  31. Felip E, Rosell R (2006) Clinical experience with erlotinib in non-small-cell lung cancer. Drugs Today (Barc) 2006, 42(3):147–156

    Article  CAS  Google Scholar 

  32. Smith J (2005) Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer. Clin Ther 27:1513–1534

    Article  PubMed  CAS  Google Scholar 

  33. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  34. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J (2005) Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 2005 11(18):6414–6421

    Article  CAS  Google Scholar 

  35. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National 863 Plan in High Technology Progress (2002AA2Z3130) and Shanghai Leading Academic Discipline Project (Project Number: B902), we thank members of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences for design and synthesis of the novel compound Zhao260054. We thank Dr Huimin Hu for helpful discussions.

Author information

Authors and Affiliations

  1. Nephrology institute of PLA, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China

    Xishan Xiong, Lili Fu, Li Wang, Houan Cai, Lin Li & Changlin Mei

  2. Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Hualiang Jiang & Wenhu Duan

Authors
  1. Xishan Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lili Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Houan Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hualiang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenhu Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Changlin Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Changlin Mei.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiong, X., Fu, L., Wang, L. et al. Antitumor activity of a novel EGFR tyrosine kinase inhibitor against human lung carcinoma in vitro and in vivo. Invest New Drugs 27, 1–11 (2009). https://doi.org/10.1007/s10637-008-9132-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-008-9132-5

Keywords

Search

Navigation