The HER2 heterodimerization inhibitor pertuzumab is active against colon cancer cells in vitro and in vivo

Aims: 60–80% of all colon cancers show an upregulation of HER1/EGFR while their HER2-expression is variable and ranges from 20% in early stages up to 80% in metastatic disease. Both HER1/EGFR and HER2 overexpression may be associated with poor prognosis. Pertuzumab is a new antibody targeting HER2 and the first member of the new class of HER-dimerization inhibitors (HDI) which inhibit ligand dependent and independent cell proliferation. So far, some antibody effect has been shown in lung and breast cancer xenografts. Efficacy of pertuzumab against colon cancer is unknown. Aim: To investigate the effect of pertuzumab in colon cancer cells in vitro and in vivo. Methods: Colon cancer cell lines were tested for HER1 and HER2 expression by Western blotting. HER2 positive SW480 and HCT115 cells were stimulated with recombinant EGF–1 (100 ng/ml) with or without pertuzumab (10mg/ml) and cell cycle distribution was measured after 24 hours. SW480 xenograft tumors were established in NMRI nude mice by bilateral subcutaneous flank injection and animals were treated intraperitoneally with 6mg/kg pertuzumab (n=6) or PBS (n=5) weekly for four weeks. Results: Eight out of ten cancer cell lines were positive for HER1/EGFR expression, but only SW480 and HCT115 cells were positive for HER2. EGF stimulation induced cell cycle progression with an increase in S- and G2-phase. However cell cycle progression was abolished upon pertuzumab treatment and cells were arrested in G1. In nude mice tumor volume was determined after 4 weeks of treatment. In the pertuzumab group response was seen in 5 animals with a mean reduction in tumor volume of 41% (11.7–80.4%). All animals in the control group and 1 animal in the treatment group showed continuous tumor growth. Mean tumor volume after 4 weeks was 68 mm3 in the treatment group and 127 mm3 in the control group. Discussion: This study shows that the HER-dimerization inhibitor pertuzumab is active against colon cancer cells in vitro and in vivo. We are presently studying the antibody in combination with standard chemotherapy in animal models. Pertuzumab may be a promising new agent for targeted therapy of metastatic colon cancer.

Keywords: pertuzumab; colon cancer; targeted therapy