title: The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272.
abstract: Mutations in the ERBB2 gene were recently found in approximately 2% of primary non-small cell lung cancer (NSCLC) specimens; however, little is known about the functional consequences and the relevance to responsiveness to targeted drugs for most of these mutations. Here, we show that the major lung cancer-derived ERBB2 mutants, including the most frequent mutation, A775insYVMA, lead to oncogenic transformation in a cellular assay. Murine cells transformed with these mutants were relatively resistant to the reversible epidermal growth factor receptor (EGFR) inhibitor erlotinib, resembling the resistant phenotype found in cells carrying the homologous mutations in exon 20 of EGFR. However, the same cells were highly sensitive to the irreversible dual-specificity EGFR/ERBB2 kinase inhibitor HKI-272, as were those overexpressing wild-type ERBB2. Finally, the NSCLC cell line, Calu-3, overexpressing wild-type ERBB2 owing to a high-level amplification of the ERBB2 gene were highly sensitive to HKI-272. These results provide a rationale for treatment of patients with ERBB2-mutant or ERBB2-amplified lung tumors with HKI-272.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Minami
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.forename: K
authors.initials: K
authors.lastname: Shah
authors.forename: T
authors.initials: T
authors.lastname: LaFramboise
authors.forename: K A
authors.initials: KA
authors.lastname: Glatt
authors.forename: E
authors.initials: E
authors.lastname: Liniker
authors.forename: C L
authors.initials: CL
authors.lastname: Borgman
authors.forename: H J
authors.initials: HJ
authors.lastname: Haringsma
authors.forename: W
authors.initials: W
authors.lastname: Feng
authors.forename: B A
authors.initials: BA
authors.lastname: Weir
authors.forename: A M
authors.initials: AM
authors.lastname: Lowell
authors.forename: J C
authors.initials: JC
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Wolf
authors.forename: G I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: K-K
authors.initials: KK
authors.lastname: Wong
authors.forename: M
authors.initials: M
authors.lastname: Meyerson
authors.forename: R K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib