PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib
JA Engelman, K Zejnullahu, CM Gale, E Lifshits… - Cancer research, 2007 - AACR
JA Engelman, K Zejnullahu, CM Gale, E Lifshits, AJ Gonzales, T Shimamura, F Zhao…
Cancer research, 2007•AACREpidermal 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 …
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 …
Abstract
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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