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.

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.

• Authors: Christel Larbouret, Nadège Gaborit, Thierry Chardès, Mickaël Coelho, Emmanuelle Campigna, Caroline Bascoul-Mollevi, Jean-Pierre Mach, David Azria, Bruno Robert, André Pèlegrin
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 14 Issue 2 Pg. 121-30 (Feb 2012) ISSN: 1476-5586 [Electronic] United States
• PMID: 22431920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Quinazolines
• Lapatinib
• Erlotinib Hydrochloride
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Trastuzumab
• Cetuximab

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinoma (drug therapy)
• Cell Line, Tumor
• Cetuximab
• Down-Regulation
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride
• Female
• Humans
• Inhibitory Concentration 50
• Kaplan-Meier Estimate
• Lapatinib
• Mice
• Mice, Nude
• Mice, SCID
• Pancreatic Neoplasms (drug therapy)
• Phosphorylation
• Protein Multimerization (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinazolines (administration & dosage, pharmacology, therapeutic use)
• Receptor, ErbB-2 (antagonists & inhibitors, genetics, metabolism)
• Trastuzumab
• Xenograft Model Antitumor Assays