title: HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.
abstract: Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Samanthi A
authors.initials: SA
authors.lastname: Perera
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Maria G
authors.initials: MG
authors.lastname: Raso
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Christa L
authors.initials: CL
authors.lastname: Borgman
authors.forename: Sara
authors.initials: S
authors.lastname: Zaghlul
authors.forename: Kathleyn A
authors.initials: KA
authors.lastname: Brandstetter
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kubo
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Guertler
authors.forename: Pilar Garin
authors.initials: PG
authors.lastname: Chesa
authors.forename: Flavio
authors.initials: F
authors.lastname: Solca
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000077716:Afatinib; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000077716:Afatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; C524056:Erbb2 protein, mouse