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

• Published in: Journal of cancer research and clinical oncology Vol. 135; no. 10; pp. 1377 - 1386
• Main Authors: Pohl, Michael, Stricker, I, Schoeneck, A, Schulmann, K, Klein-Scory, S, Schwarte-Waldhoff, I, Hasmann, M, Tannapfel, A, Schmiegel, W, Reinacher-Schick, A
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.10.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Blotting, Western; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Cancer Research; Cell Cycle - drug effects; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Dimerization; Drug Therapy, Combination; Epidermal Growth Factor - pharmacology; Erlotinib Hydrochloride; Female; Gastroenterology. Liver. Pancreas. Abdomen; Hematology; Humans; In Vitro Techniques; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Nude; Monoclonal antibodies; Oncology; Original Paper; Pharmacology. Drug treatments; Protein Multimerization - drug effects; Quinazolines - administration & dosage; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Rodents; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Xenograft Model Antitumor Assays; Irinotecan; Dual ErbB inhibition; Pertuzumab; HER dimerization inhibitor; Colorectal cancer; Antineoplastic agent; Rectal disease; erbB2 Gene; Monoclonal antibody; Isomerases; Colon cancer; Intestinal disease; Inhibition; Topoisomerase I inhibitor; Dimerization; Tumor cell; Protooncogene; Camptothecin derivatives; Human; Enzyme; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; Human Epidermal growth factor Receptor 2; Colonic disease; In vivo; C-Onc gene; Digestive diseases; Cancer
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-009-0579-3

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.