title: Development and characterization of a preclinical ovarian carcinoma             model to investigate the mechanism of acquired resistance to trastuzumab.
abstract: Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to             bind and inhibit the function of the human epidermal growth factor receptor 2             (HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several             types of HER2-overexpressing epithelial tumors, such as breast and metastatic             gastric 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 to             trastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3             Herceptin-resistant (HR), and examined the corresponding changes in gene expression             profiles. SKOV-3 HR cells were developed by in vivo serial passaging of parental             trastuzumab-sensitive SKOV-3 cells. Following four rounds of serial transplantation             of 'break-through' xenograft tumors under trastuzumab treatment, significant and             reproducible differences in the effects of trastuzumab treatment between SKOV-3 HR             and SKOV-3 cells in vivo and in vitro were revealed. SKOV-3 HR cells retained             HER2 protein expression but were unaffected by the antiproliferative effects of             trastuzumab. The trastuzumab binding affinity for SKOV-3 HR cells was diminished,             despite these cells having more binding sites for trastuzumab. Microarray expression             profiling (MEP) was performed to determine the genes involved in the resistance             mechanism. Functional analysis revealed the differential expression of genes potentially             involved in angiogenesis, metastasis, differentiation and proliferation, such             as mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrated             a marked overexpression of MUC1. Based on these data, we hypothesize that the             overexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, abrogating             the antitumor effects of trastuzumab and thus could contribute to resistance to             therapy. Moreover, the resultant MEP preclinical gene signature in this preclinical             model system may provide the basis for further investigation of potential clinical             mechanisms of resistance to trastuzumab.
authors.affiliation: Department of Discovery Oncology, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. leopoldo_l.luistro@roche.com
authors.forename: Leopoldo L
authors.initials: LL
authors.lastname: Luistro
authors.forename: James A
authors.initials: JA
authors.lastname: Rosinski
authors.forename: Hongjin
authors.initials: H
authors.lastname: Bian
authors.forename: Subal
authors.initials: S
authors.lastname: Bishayee
authors.forename: Pranela
authors.initials: P
authors.lastname: Rameshwar
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Ponzio
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ritland
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D018396:Mucin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C060192:MUC1 protein, human; C508053:ERBB2 protein, human