In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption.

Details

Serval ID
serval:BIB_E552CBE76F09
Type
Article: article from journal or magazin.
Collection
Publications
Title
In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption.
Journal
Neoplasia
Author(s)
Larbouret C., Gaborit N., Chardès T., Coelho M., Campigna E., Bascoul-Mollevi C., Mach J.P., Azria D., Robert B., Pèlegrin A.
ISSN
1476-5586 (Electronic)
ISSN-L
1476-5586
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
14
Number
2
Pages
121-130
Language
english
Notes
Publication types: Journal Article
Abstract
We previously demonstrated the synergistic therapeutic effect of the cetuximab (anti-epidermal growth factor receptor [EGFR] monoclonal antibody, mAb)-trastuzumab (anti-HER2 mAb) combination (2mAbs therapy) in HER2(low) human pancreatic carcinoma xenografts. Here, we compared the 2mAbs therapy, the erlotinib (EGFR tyrosine kinase inhibitor [TKI])-trastuzumab combination and lapatinib alone (dual HER2/EGFR TKI) and explored their possible mechanisms of action. The effects on tumor growth and animal survival of the three therapies were assessed in nude mice xenografted with the human pancreatic carcinoma cell lines Capan-1 and BxPC-3. After therapy, EGFR and HER2 expression and AKT phosphorylation in tumor cells were analyzed by Western blot analysis. EGFR/HER2 heterodimerization was quantified in BxPC-3 cells by time-resolved FRET. In K-ras-mutated Capan-1 xenografts, the 2mAbs therapy gave significantly higher inhibition of tumor growth than the erlotinib/trastuzumab combination, whereas in BxPC-3 (wild-type K-ras) xenografts, the erlotinib/trastuzumab combination showed similar growth inhibition but fewer tumor-free mice. Lapatinib showed no antitumor effect in both types of xenografts. The efficacy of the 2mAbs therapy was partly Fc-independent because F(ab')(2) fragments of the two mAbs significantly inhibited BxPC-3 growth, although with a time-limited therapeutic effect. The 2mAbs therapy was associated with a reduction of EGFR and HER2 expression and AKT phosphorylation. BxPC-3 cells preincubated with the two mAbs showed 50% less EGFR/HER2 heterodimers than controls. In pancreatic carcinoma xenografts, the 2mAbs therapy is more effective than treatments involving dual EGFR/HER2 TKIs. The mechanism of action may involve decreased AKT phosphorylation and/or disruption of EGFR/HER2 heterodimerization.
Keywords
Animals, Antibodies, Monoclonal/administration & dosage, Antibodies, Monoclonal, Humanized/administration & dosage, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carcinoma/drug therapy, Cell Line, Tumor, Down-Regulation, Female, Humans, Inhibitory Concentration 50, Kaplan-Meier Estimate, Mice, Mice, Nude, Mice, SCID, Pancreatic Neoplasms/drug therapy, Phosphorylation, Protein Multimerization/drug effects, Proto-Oncogene Proteins c-akt/metabolism, Quinazolines/administration & dosage, Quinazolines/pharmacology, Receptor, Epidermal Growth Factor/antagonists & inhibitors, Receptor, Epidermal Growth Factor/genetics, Receptor, erbB-2/antagonists & inhibitors, Receptor, erbB-2/genetics, Xenograft Model Antitumor Assays
Pubmed
Web of science
Create date
28/04/2012 13:23
Last modification date
20/08/2019 17:08
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