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.
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Authors | Jeffrey A Engelman, Kreshnik Zejnullahu, Christopher-Michael Gale, Eugene Lifshits, Andrea J Gonzales, Takeshi Shimamura, Feng Zhao, Patrick W Vincent, George N Naumov, James E Bradner, Irene W Althaus, Leena Gandhi, Geoffrey I Shapiro, James M Nelson, John V Heymach, Matthew Meyerson, Kwok-Kin Wong, Pasi A Jänne |
Journal | Cancer research
(Cancer Res)
Vol. 67
Issue 24
Pg. 11924-32
(Dec 15 2007)
ISSN: 1538-7445 [Electronic] United States |
PMID | 18089823
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Antineoplastic Agents
- ERBIN protein, human
- Oncogene Proteins v-erbB
- Quinazolines
- Quinazolinones
- dacomitinib
- ErbB Receptors
- Gefitinib
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Topics |
- Adaptor Proteins, Signal Transducing
(drug effects, genetics)
- Animals
- Antineoplastic Agents
(therapeutic use)
- Cell Division
- Cell Line, Tumor
- Cloning, Molecular
- ErbB Receptors
(drug effects, genetics)
- Gefitinib
- Humans
- Lung Neoplasms
- Mice
- Mice, Nude
- Oncogene Proteins v-erbB
(antagonists & inhibitors)
- Quinazolines
(pharmacology)
- Quinazolinones
(therapeutic use)
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