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PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib

¹ Massachusetts General Hospital Cancer Center; ² Department of Systems Biology, Harvard Medical School; ³ Department of Signal Transduction, Beth Israel Deaconess Medical Center; ⁴ Lowe Center for Thoracic Oncology and ⁵ Department of Medical Oncology, Dana-Farber Cancer Institute; ⁶ Department of Surgery and Vascular Biology Program, Children's Hospital; ⁷ Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School; ⁸ Department of Pathology, Harvard Medical School, Boston, Massachusetts; ⁹ Pfizer Global Research and Development, Cancer Drug Discovery, Ann Arbor, Michigan; ¹⁰ Pfizer Global Research and Development, Groton, Connecticut; ¹¹ Department of Thoracic/Head and Neck Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ¹² The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts

Requests for reprints: Pasi A. Jänne, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D820A, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6076; Fax: 617-582-7683; E-mail: pjanne{at}partners.org.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non–small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members. [Cancer Res 2007;67(24):11924–32]

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