Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer☆
Introduction
Gastric cancer is one of the most frequent human malignancies and the second leading cause of cancer-related death in the world [1]. Because the early disease is often asymptomatic, many gastric cancer patients are diagnosed when their cancer is already beyond curative surgery [2], [3]. Treatment options for these patients include radiotherapy and chemotherapy, but cancer progression is common and the 5-year survival rate is less than 30% [2], [3]. Therefore, a high unmet medical need exists to develop new highly potent therapies.
One possible target is HER2 (ErbB2) oncoprotein, a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Its overexpression occurs in ∼20% of gastric cancers and is associated with poor clinical outcome [4], [5]. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of HER2, has shown significant antitumor effect in both in vitro and in vivo models of HER2-positive gastric cancer [4], [5], [6], [7], [8]. Very recently, a randomized phase III clinical trial (ToGA trial) showed that trastuzumab is highly effective in untreated advanced HER2-positive gastric cancer patients and significantly improved overall survival when given in combination with standard chemotherapy [9]. These data show that trastuzumab is a valuable drug for the treatment of the HER2-positive subset of gastric cancers. Unfortunately, a sizable fraction of HER2-positive patients in the ToGA trial did progress on treatment [9], [10]. This denotes that developing trastuzumab resistance might be a problem also in gastric cancer, similar to the situation in breast cancer [11]. For this reason, several research strategies have focused on alternative HER2 directed treatments.
A new strategy of anti-HER2 targeted therapy has been achieved using the antibody–drug conjugate technology. The monoclonal antibody trastuzumab has been conjugated with cytotoxic molecule DM1 (derivative of maytansine 1). The resulting conjugate, named trastuzumab-DM1 (T-DM1) is designed to deliver the highly potent DM1 into the HER2 overexpressing cells via receptor-mediated endocytosis [12]. Active lysine-mcc-DM1 is released by lysosomal degradation [13]. Free intracellular DM1 is a potent inhibitor of microtubule assembly thereby causing cell death [14], [15]. T-DM1 is effective both in vitro and in vivo models of trastuzumab-insensitive breast cancer [12], furthermore, it showed remarkable activity in phase I and II studies in which it was given to patients with trastuzumab-insensitive HER2-positive breast cancer [16], [17], [18].
Because trastuzumab is effective in HER2-positive gastric cancer, and T-DM1 shows promising efficacy in trastuzumab insensitive breast cancer, we wanted to test the efficacy and mechanisms of T-DM1 on gastric cancer cell models. In this paper we report that T-DM1 displayed strong anti-tumor effect in OE-19 and N-87 gastric cancer in vitro and in xenograft tumors in vivo. Furthermore, T-DM1 was highly effective even on large tumors which progressed on prior trastuzumab. This is the first study which shows the efficacy of T-DM1 on gastric cancer cells in vivo.
Section snippets
Cells
OE-19 human gastric cancer cell line was obtained from the European Collection of Cell Culture (CAMR Centre for Applied Microbiology and Research, Wiltshire, United Kingdom). MKN-7 and N-87 human gastric cancer cell lines were obtained from American Type Culture Collection (ATCC, Manassas, VA). SNU-216 human gastric cancer cell line was obtained from the Korean Cell Line Bank (Seoul, Korea). Human breast cancer cell lines MCF-7 and SKBR-3 (ATCC) were used as a control. The cell lines were
HER2 oncogene amplification and protein expression levels of human gastric cancer cell lines
Using FISH analysis we confirmed that the HER2 oncogene is amplified in all gastric cancer cell lines studied. By flow cytometric analysis we showed that HER2 protein is highly overexpressed in N-87 and OE-19, comparable to that of breast cancer cell line SKBR-3. HER2 protein in MKN-7 and SNU-216 cells was also overexpressed, being about one third of that in N-87 and OE-19 (Table 1). Conjugation of trastuzumab with DM1 did not influence of binding to the OE19 gastric cancer cells (Fig. 1A).
Trastuzumab- and T-DM1-mediated ADCC against HER2-positive gastric cancer cells
Discussion
Trastuzumab-DM1 (T-DM1) is a new antibody–drug conjugate which has been developed to improve the therapy of HER2-positive breast cancer. So far T-DM1 has not been extensively studied in preclinical models of gastric cancer. In this study, we showed the efficacy of T-DM1 on gastric cancer xenograft tumors.
We applied different treatment strategies when testing T-DM1 in tumor xenografts. A complete pathological response was observed in all of the OE-19 xenografts and in half of the N-87 xenografts
Conflict of interest
The authors disclose no financial conflicts of interest that could influence the present work.
Role of the funding source
This study was financially supported by the Tampere University Hospital Research Foundation, Academy of Finland, Sigrid Juselius Foundation and Finnish Cancer Foundation. The sponsors had no influence on the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
Acknowledgements
The skillful technical assistance of Ms. Kristiina Ryömä, Mrs. Sari Toivola and Ms. Barbara Német is greatly appreciated. We thank Genentech Inc. for providing T-DM1.
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Author contributions: B.M., M.T. and J.I. conceived and designed the experiments; B.M. and K.K. performed the experiments; B.M. and J.I. analyzed data; and B.M. and J.I. wrote the paper.