PMID- 24898067
OWN - NLM
STAT- MEDLINE
DCOM- 20150112
LR  - 20220408
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 13
DP  - 2014 Jun 5
TI  - Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and 
      overcomes gefitinib resistance.
PG  - 143
LID - 10.1186/1476-4598-13-143 [doi]
AB  - BACKGROUND: HER-2 represents a relatively new therapeutic target for non small 
      cell lung cancer (NSCLC) patients. The incidence for reported HER-2 
      overexpression/amplification/mutations ranges from 2 to 20% in NSCLC. Moreover, 
      HER-2 amplification is a potential mechanism of resistance to tyrosine kinase 
      inhibitors of the epidermal growth factor receptor (EGFR-TKI) (about 10% of 
      cases). T-DM1, trastuzumab emtansine is an antibody-drug conjugate composed by 
      the monoclonal antibody trastuzumab and the microtubule polymerization inhibitor 
      DM1. The activity of T-DM1 has been studied in breast cancer but the role of 
      T-DM1 in lung cancer remains unexplored. METHODS: Antiproliferative and 
      proapoptotic effects of T-DM1 have been investigated in different NSCLC cell 
      lines by MTT, crystal violet staining, morphological study and Western blotting. 
      HER-2 expression and cell cycle were evaluated by flow cytometry and Western 
      blotting. Antibody dependent cell cytotoxicity (ADCC) was measured with a CytoTox 
      assay. Xenografted mice model has been generated using a NSCLC cell line to 
      evaluate the effect of T-DM1 on tumor growth. Moreover, a morphometric and 
      immunohistochemical analysis of tumor xenografts was conducted. RESULTS: In this 
      study we investigated the effect of T-DM1 in a panel of NSCLC cell lines with 
      different HER-2 expression levels, in H1781 cell line carrying HER-2 mutation and 
      in gefitinib resistant HER-2 overexpressing PC9/HER2cl1 cell clone. T-DM1 
      efficiently inhibited proliferation with arrest in G2-M phase and induced cell 
      death by apoptosis in cells with a significant level of surface expression of 
      HER-2. Antibody-dependent cytotoxicity assay documented that T-DM1 maintained the 
      same activity of trastuzumab. Our data also suggest that targeting HER-2 with 
      T-DM1 potentially overcomes gefitinib resistance. In addition a correlation 
      between cell density/tumor size with both HER-2 expression and T-DM1 activity was 
      established in vitro and in an in vivo xenograft model. CONCLUSIONS: Our results 
      indicate that targeting HER-2 with T-DM1 may offer a new therapeutic approach in 
      HER-2 over-expressing lung cancers including those resistant to EGFR TKIs.
FAU - Cretella, Daniele
AU  - Cretella D
FAU - Saccani, Francesca
AU  - Saccani F
FAU - Quaini, Federico
AU  - Quaini F
FAU - Frati, Caterina
AU  - Frati C
FAU - Lagrasta, Costanza
AU  - Lagrasta C
FAU - Bonelli, Mara
AU  - Bonelli M
FAU - Caffarra, Cristina
AU  - Caffarra C
FAU - Cavazzoni, Andrea
AU  - Cavazzoni A
FAU - Fumarola, Claudia
AU  - Fumarola C
FAU - Galetti, Maricla
AU  - Galetti M
FAU - La Monica, Silvia
AU  - La Monica S
FAU - Ampollini, Luca
AU  - Ampollini L
FAU - Tiseo, Marcello
AU  - Tiseo M
FAU - Ardizzoni, Andrea
AU  - Ardizzoni A
FAU - Petronini, Pier Giorgio
AU  - Petronini PG
FAU - Alfieri, Roberta R
AU  - Alfieri RR
AD  - Department of Clinical and Experimental Medicine, University of Parma, Via 
      Gramsci 14, Parma, 43126, Italy. roberta.alfieri@unipr.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140605
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunoconjugates)
RN  - 0 (Quinazolines)
RN  - 14083FR882 (Maytansine)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/chemistry/*pharmacology
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Female
MH  - Gefitinib
MH  - Gene Expression
MH  - Humans
MH  - Immunoconjugates/chemistry/*pharmacology
MH  - Lung Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Maytansine/*analogs & derivatives/chemistry/pharmacology
MH  - Mice
MH  - Mice, Nude
MH  - Quinazolines/pharmacology
MH  - Receptor, ErbB-2/*genetics/metabolism
MH  - Trastuzumab
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4058446
EDAT- 2014/06/06 06:00
MHDA- 2015/01/13 06:00
PMCR- 2014/06/05
CRDT- 2014/06/06 06:00
PHST- 2014/04/07 00:00 [received]
PHST- 2014/05/30 00:00 [accepted]
PHST- 2014/06/06 06:00 [entrez]
PHST- 2014/06/06 06:00 [pubmed]
PHST- 2015/01/13 06:00 [medline]
PHST- 2014/06/05 00:00 [pmc-release]
AID - 1476-4598-13-143 [pii]
AID - 10.1186/1476-4598-13-143 [doi]
PST - epublish
SO  - Mol Cancer. 2014 Jun 5;13:143. doi: 10.1186/1476-4598-13-143.