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BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models

Abstract

Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.

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References

  • Bedano PM, Hanna NH . (2006). Salvage therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol 1: 582–587.

    Article  PubMed  Google Scholar 

  • Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J et al. (1985). Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132–1139.

    Article  CAS  PubMed  Google Scholar 

  • Engelman JA, Jänne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C et al. (2005). ErbB-3 mediates PI3K activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102: 3788–3793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039–1043.

    Article  CAS  PubMed  Google Scholar 

  • Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H et al. (2008). A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98: 80–85.

    Article  CAS  PubMed  Google Scholar 

  • Fan Z, Baselga J, Masui H, Mendelsohn J . (1993). Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53: 4637–4642.

    CAS  PubMed  Google Scholar 

  • Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M et al. (2005). Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2: e313.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hurwitz E, Klapper LN, Wilchek M, Yarden Y, Sela M . (2000). Inhibition of tumor growth by poly(ethylene glycol) derivatives of anti-ErbB2 antibodies. Cancer Immunol Immunother 49: 226–234.

    Article  CAS  PubMed  Google Scholar 

  • Hynes NE, Lane HA . (2005). ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5: 341–354.

    Article  CAS  PubMed  Google Scholar 

  • Janne PA, Engelman JA, Johnson BE . (2005). Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23: 3227–3234.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K et al. (2006a). The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9: 485–495.

    Article  CAS  PubMed  Google Scholar 

  • Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A et al. (2006b). Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci USA 103: 7817–7822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang J, Greulich H, Janne PA, Sellers WR, Meyerson M, Griffin JD . (2005). Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Res 65: 8968–8974.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M et al. (2005a). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352: 786–792.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG et al. (2005b). An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 65: 7096–7101.

    Article  CAS  PubMed  Google Scholar 

  • Krypuy M, Newnham GM, Thomas DM, Conron M, Dobrovic A . (2006). High resolution melting analysis for the rapid and sensitive detection of mutations in clinical samples: KRAS codon 12 and 13 mutations in non-small cell lung cancer. BMC Cancer 6: 295.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW et al. (2005). Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102: 7665–7670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, Debiasi RM et al. (2006). Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3: e485.

    Article  PubMed  PubMed Central  Google Scholar 

  • Li D, Ji H, Zaghlul S, McNamara K, Liang MC, Shimamura T et al. (2007a). Therapeutic anti-EGFR antibody 806 generates responses in murine de novo EGFR mutant-dependent lung carcinomas. J Clin Invest 117: 346–352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li D, Shimamura T, Ji H, Chen L, Haringsma HJ, McNamara K et al. (2007b). Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12: 81–93.

    Article  CAS  PubMed  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. (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  CAS  PubMed  Google Scholar 

  • Mulloy R, Ferrand A, Kim Y, Sordella R, Bell DW, Haber DA et al. (2007). Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Cancer Res 67: 2325–2330.

    Article  CAS  PubMed  Google Scholar 

  • Paez JG, Janne PA, Lee JC, 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.

    Article  CAS  PubMed  Google Scholar 

  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et al. (2004). EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101: 13306–13311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF et al. (2005a). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib Is associated with a second mutation in the EGFR kinase domain. PLoS Med 2: e73.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M et al. (2005b). KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2: e17.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J et al. (2004). Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64: 3958–3965.

    Article  CAS  PubMed  Google Scholar 

  • Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES et al. (2006). Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 12: 839–844.

    Article  CAS  PubMed  Google Scholar 

  • Schiffer HH, Reding EC, Fuhs SR, Lu Q, Piu F, Wong S et al. (2007). Pharmacology and signaling properties of epidermal growth factor receptor isoforms studied by bioluminescence resonance energy transfer. Mol Pharmacol 71: 508–518.

    Article  CAS  PubMed  Google Scholar 

  • Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H et al. (2005). Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65: 1642–1646.

    Article  CAS  PubMed  Google Scholar 

  • Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K et al. (2006). Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res 66: 6487–6491.

    Article  CAS  PubMed  Google Scholar 

  • Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J et al. (2004). Lung cancer: intragenic ERBB2 kinase mutations in tumors. Nature 431: 525–526.

    Article  CAS  PubMed  Google Scholar 

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW et al. (1984). Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309: 418–425.

    Article  CAS  PubMed  Google Scholar 

  • Vikis H, Sato M, James M, Wang D, Wang Y, Wang M et al. (2007). EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer Res 67: 4665–4670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S et al. (2006). HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10: 25–38.

    Article  PubMed  Google Scholar 

  • Yuza Y, Glatt KA, Jiang J, Greulich H, Minami Y, Woo MS et al. (2007). Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors. Cancer Biol Ther 6: 661–667.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Jeffrey Whitsett for providing the CCSP-rtTA transgenic mice. We also thank all present and past members of the BIBW2992 research and development team at Boehringer Ingelheim Austria GmbH and Boehringer Ingelheim Pharma GmbH & Co. KG for their respective contributions. In particular, we acknowledge Ursula Strobl, Monika Leber, Reiner Meyer, Regina Ruzicka, Franziska Popp, Christine Lam and Mei Zheng for their commitment and excellent technical assistance. TS was supported by a Career Development Award as part of the Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Lung Cancer, NIH Grant P20 CA90578. GIS was supported by NIH Grants P20 CA90578 and R01 CA90687. KKW was supported by NIH Grant K08 AG024004, R01 CA122794, R01 AG2400401, the Sidney Kimmel Foundation for Cancer Research, the Joan Scarangello Foundation to Conquer Lung Cancer, the Cecily and Robert Harris Foundation and the Flight Attendant Medical Research Institute.

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Correspondence to F Solca.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Li, D., Ambrogio, L., Shimamura, T. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702–4711 (2008). https://doi.org/10.1038/onc.2008.109

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