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Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed tobind and inhibit the function of the human epidermal growth factor receptor 2(HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in severaltypes of HER2-overexpressing epithelial tumors, such as breast and metastaticgastric or gastroesophageal junction cancer. Relapse and therapeutic resistance,however, still occur in a subset of patients treated with regimens including trastuzumab,despite significant improvements in response rates, survival and quality of life.To investigate the potential mechanisms of acquired therapeutic resistance totrastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3Herceptin-resistant (HR), and examined the corresponding changes in gene expressionprofiles. SKOV-3 HR cells were developed by in vivo serial passaging of parentaltrastuzumab-sensitive SKOV-3 cells. Following four rounds of serial transplantationof 'break-through' xenograft tumors under trastuzumab treatment, significant andreproducible differences in the effects of trastuzumab treatment between SKOV-3 HRand SKOV-3 cells in vivo and in vitro were revealed. SKOV-3 HR cells retainedHER2 protein expression but were unaffected by the antiproliferative effects oftrastuzumab. The trastuzumab binding affinity for SKOV-3 HR cells was diminished,despite these cells having more binding sites for trastuzumab. Microarray expressionprofiling (MEP) was performed to determine the genes involved in the resistancemechanism. Functional analysis revealed the differential expression of genes potentiallyinvolved in angiogenesis, metastasis, differentiation and proliferation, suchas mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrateda marked overexpression of MUC1. Based on these data, we hypothesize that theoverexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, abrogatingthe antitumor effects of trastuzumab and thus could contribute to resistance totherapy. Moreover, the resultant MEP preclinical gene signature in this preclinicalmodel system may provide the basis for further investigation of potential clinicalmechanisms of resistance to trastuzumab.

Development and characterization of a preclinical ovarian carcinoma model to investigate the mechanism of acquired resistance to trastuzumab