PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib

Cancer Res. 2007 Dec 15;67(24):11924-32. doi: 10.1158/0008-5472.CAN-07-1885.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / drug effects
  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cell Division
  • Cell Line, Tumor
  • Cloning, Molecular
  • ErbB Receptors / drug effects
  • ErbB Receptors / genetics*
  • Gefitinib
  • Humans
  • Lung Neoplasms
  • Mice
  • Mice, Nude
  • Oncogene Proteins v-erbB / antagonists & inhibitors*
  • Quinazolines / pharmacology*
  • Quinazolinones / therapeutic use*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • ERBIN protein, human
  • Oncogene Proteins v-erbB
  • Quinazolines
  • Quinazolinones
  • dacomitinib
  • ErbB Receptors
  • Gefitinib