Details

Autor(en) / Beteiligte

• ENGELMAN, Jeffrey A
• ZEJNULLAHU, Kreshnik
• ALTHAUS, Irene W
• GANDHI, Leena
• SHAPIRO, Geoffrey I
• NELSON, James M
• HEYMACH, John V
• MEYERSON, Matthew
• WONG, Kwok-Kin
• JÄNNE, Pasi A
• GALE, Christopher-Michael
• LIFSHITS, Eugene
• GONZALES, Andrea J
• SHIMAMURA, Takeshi
• FENG ZHAO
• VINCENT, Patrick W
• NAUMOV, George N
• BRADNER, James E

Titel

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

Ist Teil von

• Cancer research (Chicago, Ill.), 2007-12, Vol.67 (24), p.11924-11932

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.