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In vivo Therapeutic Synergism of Anti–Epidermal Growth Factor Receptor and Anti-HER2 Monoclonal Antibodies against Pancreatic Carcinomas

Authors' Affiliations: ¹ Institut National de la Santé et de la Reserche Médicale, EMI 0227, Centre de Recherche en cancérologie de Montpellier, Université Montpellier I; CRLC Val d' Aurelle-Paul Lamarque; ² Unité de biostatistiques; and ³ Département de pathologie, and ⁴ Département de radiothérapie, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France; and ⁵ Département de Biochimie, Université de Lausanne, Epalinges, Switzerland

Requests for reprints: André Pèlegrin, Centre de Recherche en Cancérologie de Montpellier, Centre Régional de Lutte Contre le Cancer Val d'Aurelle-Paul Lamarque, 34298 Montpellier Cedex 5, France. Phone: 33-467-613-032; Fax: 33-467-613-787; E-mail: apelegrin{at}valdorel.fnclcc.fr.

Purpose: Pancreatic carcinoma is highly resistant to therapy. Epidermal growth factor receptor (EGFR) and HER2 have been reported to be both dysregulated in this cancer. To evaluate the in vivo effect of binding both EGFR and HER2 with two therapeutic humanized monoclonal antibodies (mAb), we treated human pancreatic carcinoma xenografts, expressing high EGFR and low HER2 levels.

Experimental Design: Nude mice, bearing xenografts of BxPC-3 or MiaPaCa-2 human pancreatic carcinoma cell lines, were injected twice weekly for 4 weeks with different doses of anti-EGFR (matuzumab) and anti-HER2 (trastuzumab) mAbs either alone or in combination. The effect of the two mAbs, on HER receptor phosphorylation, was also studied in vitro by Western blot analysis.

Results: The combined mAb treatment significantly inhibited tumor progression of the BxPC-3 xenografts compared with single mAb injection (P = 0.006) or no treatment (P = 0.0004) and specifically induced some complete remissions. The two mAbs had more antitumor effect than 4-fold greater doses of each mAb. The significant synergistic effect of the two mAbs was confirmed on the MiaPaCa-2 xenograft and on another type of carcinoma, SK-OV-3 ovarian carcinoma xenografts. In vitro, the cooperative effect of the two mAbs was associated with a decrease in EGFR and HER2 receptor phosphorylation.

Conclusions: Anti-HER2 mAb has a synergistic therapeutic effect when combined with an anti-EGFR mAb on pancreatic carcinomas with low HER2 expression. These observations may open the way to the use of these two mAbs in a large panel of carcinomas expressing different levels of the two HER receptors.