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Antitumor activity of the HER2 dimerization inhibitor pertuzumab on human colon cancer cells in vitro and in vivo

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Abstract

Purpose

The monoclonal antibody pertuzumab represents the first HER2 dimerization inhibitor with unknown activity in colon cancer treatment. We examined the antitumor activity of pertuzumab as a single agent or in combination with erlotinib or irinotecan in human colon cancer cells in vitro and in vivo.

Methods

Colon cancer cell lines were tested for HER1/HER2 expression by western blot analysis. The effect of pertuzumab on cell cycle distribution was analyzed by FACS. Nude mice bearing xenograft tumors were treated with pertuzumab alone, or in combination either with irinotecan or with erlotinib. Tumor volume was measured repeatedly. Tumor histology was analyzed for necrosis.

Results

Six of nine cell lines showed high expression of HER1/HER2. Pertuzumab inhibited cell cycle progression in various cell lines. Pertuzumab showed minor antitumor activity in xenograft tumors, but significantly inhibited tumor growth when combined with erlotinib (P < 0.001). Combination of pertuzumab with irinotecan had no additional effect on growth of additional tumors. Pertuzumab treated DLD-1 xenograft tumors did not show enhanced necrosis, which, however, was found in HCT116 derived xenografts.

Conclusions

Pertuzumab has some antitumor activity on human colon cancer cells in vitro and in vivo, in particular when combined with erlotinib. In vivo, pertuzumab combination treatment was not superior to irinotecan monotherapy. These data warrant further investigation of simultaneous HER1/EGFR TKI inhibition and HER1/HER2 dimerization inhibition for colorectal cancer therapy.

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Abbreviations

HER:

Human epidermal growth factor receptor

EGFR:

Epidermal growth factor receptor

MAPK:

Mitogen-activated protein kinase

TKI:

Tyrosine kinase inhibitor

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Acknowledgments

The compounds erlotinib and pertuzumab were supplied by Roche Diagnostics GmbH, Penzberg, Germany. This work was supported by grants from the “Forschungsförderung der Ruhr-Universität” (FoRUM), Germany.

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Correspondence to Michael Pohl.

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Pohl, M., Stricker, I., Schoeneck, A. et al. Antitumor activity of the HER2 dimerization inhibitor pertuzumab on human colon cancer cells in vitro and in vivo. J Cancer Res Clin Oncol 135, 1377–1386 (2009). https://doi.org/10.1007/s00432-009-0579-3

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  • DOI: https://doi.org/10.1007/s00432-009-0579-3

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