Ein inaktiver Rezeptor verhindert ein effektives EGF-Rezeptor-Targeting beim experimentellen Magenkarzinom

Abstract

Overexpression of epidermal growth factor receptor 1 (EGFR1) plays a central role in malignant transformation and tumor progression. EGFR1 inhibition by specific antibodies or tyrosine-kinase inhibitors yielded therapeutic effects in colon and lung cancer. This study evaluated the effect of EGFR1 inhibition alone or in combination with chemotherapy on human gastric cancer cell lines in vitro and in an orthotopic nude mouse model. 3 human gastric cancer cell lines (MKN-45, AGS, NCI-N87) were exposed to Carboplatin (0–3000 μg/ml), Irinotecan (0–1000 μg/ml), Docetaxel (0–300 μg/ml), or to the EGFR1-antibody Cetuximab (0–100 μg/ml) and the EGFR-tyrosine-kinase inhibitor Erlotinib (0–10 μM). Cell proliferation was assessed after 24 hours by MTT-assay. 1 cmm fragments from subcutaneous MKN-45 donor tumors were implanted into the gastric corpus of 48 nude mice. The application of Carboplatin (20 mg/kg, weekly ip.), Cetuximab (1 mg, weekly ip.) or the combination of both substances started 4 weeks after tumor induction and was continued for 14 weeks or until death. Primary tumor volume, local infiltration and metastatic spread (dissemination score) were determined at autopsy. All cell lines were evaluated for receptor status, K-Ras and Raf mutations. Carboplatin was most effective among the evaluated chemotherapeutics and reduced proliferation of gastric cancer cells in a dose dependent manner (MKN-45: –81 %; AGS: –57 %; NCI-N87: –67 %). High concentrations of the EGFR1 inhibitors Cetuximab and Erlotinib only reduced proliferation of MKN-45 cells (–16 % and –17 %, respectively). Carboplatin, Cetuximab or the combination of both substances did not exert an effect in vivo, when therapy was started 4 weeks after tumor induction. An inactive EGFR1 in MKN-45 cells may be a possible explanation for lacking effects of the EGFR1 inhibitors.