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

Abstract

<div>Abstract<p>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 <i>EGFR</i>-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 <i>EGFR</i> 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 <i>EGFR</i>-activating mutations as well as the <i>EGFR</i> T790M resistance mutation both <i>in vitro</i> and <i>in vivo</i>. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type <i>ERBB2</i> and the gefitinib-resistant oncogenic <i>ERBB2</i> 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]</p></div>