Genetic alterations in the kinase domain of the epidermal growth factor receptor 
(EGFR) in non-small cell lung cancer (NSCLC) patients are associated with 
sensitivity to treatment with small molecule tyrosine kinase inhibitors. 
Although first-generation reversible, ATP-competitive inhibitors showed 
encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR 
mutations, almost all patients developed resistance to these inhibitors over 
time. Such resistance to first-generation EGFR inhibitors was frequently linked 
to an acquired T790M point mutation in the kinase domain of EGFR, or 
upregulation of signaling pathways downstream of HER3. Overcoming these 
mechanisms of resistance, as well as primary resistance to reversible EGFR 
inhibitors driven by a subset of EGFR mutations, will be necessary for 
development of an effective targeted therapy regimen. Here, we show that 
BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, 
potently suppresses the kinase activity of wild-type and activated EGFR and HER2 
mutants, including erlotinib-resistant isoforms. Consistent with this activity, 
BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits 
survival of cancer cell lines and induces tumor regression in xenograft and 
transgenic lung cancer models, with superior activity over erlotinib. These 
findings encourage further testing of BIBW2992 in lung cancer patients harboring 
EGFR or HER2 oncogenes.