title: Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272.
abstract: Mutation-specific cancer therapy has shown promising clinical efficacy. In non-small-cell lung cancer (NSCLC), the presence of mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase correlates with clinical response to small-molecule tyrosine kinase inhibitors. Here, we show that cells harboring the G776insV_G/C mutation in the related ERBB2 tyrosine kinase (also known as HER2 or Neu), present in a small percentage of NSCLCs, are sensitive to HKI-272, an irreversible dual-specific kinase inhibitor targeting both EGFR and ERBB2. In the ERBB2-mutant NCI-H1781 cell line, HKI-272 treatment inhibited proliferation by induction of G(1) arrest and apoptotic cell death. Furthermore, HKI-272 abrogated autophosphorylation of both ERBB2 and EGFR. Finally, Ba/F3 murine pro-B cells, engineered to express mutant ERBB2, became independent of interleukin-3 and sensitive to HKI-272. Thus, the subset of NSCLC patients with tumors carrying the ERBB2 G776insV_G/C mutation may benefit from treatment with HKI-272.
authors.affiliation: Department of Medical Oncology and Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Yuko
authors.initials: Y
authors.lastname: Minami
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: April M
authors.initials: AM
authors.lastname: Lowell
authors.forename: Kinjal
authors.initials: K
authors.lastname: Shah
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Karen A
authors.initials: KA
authors.lastname: Glatt
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007377:Interleukin-3 / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D007377:Interleukin-3; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib