PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib
PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib
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DOI：
10.1158/0008-5472.can-07-1885
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发表时间：
2007-12-15
期刊：
影响因子：
11.2
通讯作者：
Janne, Pasi A.
中科院分区：
文献类型：
--
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼和厄洛替尼是非小细胞肺癌子集的有效治疗方法。特别是，具有特定EGFR激活突变的癌症似乎对这些药物最敏感。但是，尽管它们最初的反应，但这种癌症几乎总是会产生抗药性。在50％的癌症中，已经确定了二次EGFR突变T790M，可以使吉非替尼和erlotinib对EGFR激酶活性的无效抑制剂无效。因此，有临床需要开发新型的EGFR抑制剂，这些抑制剂可能有效地使含T790M的EGFR蛋白失活。在这项研究中，我们评估了一种新型化合物PF00299804（一种不可逆转的pan-ERBB抑制剂）的有效性。这些研究的结果表明，PF00299804是EGFR激活突变的有效抑制剂，以及EGFR T790M的耐药性突变，包括体外和体内。此外，PF00299804是野生型ERBB2和抗gefitinib耐gefitinib的抗性eRBB2突变的高效抑制剂。这些临床前评估支持PF00299804的进一步临床开发，用于具有ERBB家族成员突变和/或扩增的癌症。
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.