title: BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Ambrogio
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.forename: S
authors.initials: S
authors.lastname: Kubo
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: L R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: R F
authors.initials: RF
authors.lastname: Padera
authors.forename: G I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: A
authors.initials: A
authors.lastname: Baum
authors.forename: F
authors.initials: F
authors.lastname: Himmelsbach
authors.forename: W J
authors.initials: WJ
authors.lastname: Rettig
authors.forename: M
authors.initials: M
authors.lastname: Meyerson
authors.forename: F
authors.initials: F
authors.lastname: Solca
authors.forename: H
authors.initials: H
authors.lastname: Greulich
authors.forename: K-K
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human