1. ¹Department of Medical Oncology, Dana-Farber Cancer Institute, MA, USA
2. ²Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA, USA
3. ³The Broad Institute of Harvard and MIT, Cambridge, MA, USA
4. ⁴Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
5. ⁵Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA
6. ⁶Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
7. ⁷Boehringer Ingelheim Austria, Vienna, Austria
8. ⁸Boehringer Ingelheim Pharma, Biberach, Germany

Correspondence: Dr F Solca, Department of Pharmacology, Boehringer Ingelheim Austria, Dr Boehringer Gasse 5–11, Vienna, Austria. E-mail: flavio.solca@vie.boehringer-ingelheim.com

⁹These laboratories contributed equally to this work.

Received 2 January 2008; Revised 18 February 2008; Accepted 1 March 2008; Published online 14 April 2008.

Abstract

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.