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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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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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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DOI: https://doi.org/10.1038/onc.2008.109
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