Preclinical ReportsTrastuzumab in combination with paclitaxel enhances antitumor activity by promoting apoptosis in human epidermal growth factor receptor 2-positive trastuzumab-resistant gastric cancer xenograft modelsShu, Seia; Yamashita-Kashima, Yorikoa; Yanagisawa, Miekoa; Nakanishi, Hayaob; Kodera, Yasuhiroc; Harada, Naokia; Yoshimura, YasushiaAuthor Information aProduct Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura bLaboratory of Pathology and Clinical Research, Aichi Cancer Center, Aichi Hospital, Okazaki cDepartment of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan Received 23 April 2019 Revised form accepted 16 September 2019 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.anti-cancerdrugs.com. Correspondence to Naoki Harada, PhD, Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan, Tel: +81 467 45 7692; fax: +81 467 45 7643; e-mail: email@example.com Anti-Cancer Drugs: March 2020 - Volume 31 - Issue 3 - p 241-250 doi: 10.1097/CAD.0000000000000853 Buy SDC Metrics Abstract Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 antibody drug, is the first-line therapy for human epidermal growth factor receptor 2-positive breast and gastric cancer. For breast cancer, the benefit of continuous treatment with trastuzumab after it becomes refractory to first-line therapy has been demonstrated. However, it is unclear whether trastuzumab can show similar efficacy as a second-line treatment for gastric cancer. Here, we report that trastuzumab in combination with paclitaxel exhibits increased antitumor efficacy even for trastuzumab-resistant xenografted tumors. We derived the trastuzumab-resistant models from previously established human epidermal growth factor receptor 2-positive gastric cancer patient-derived cells. Human epidermal growth factor receptor 2 expression, PIK3CA mutation, and phosphatase and tensin homolog expression in these resistant models was equivalent to those in the trastuzumab-sensitive parental model, whereas cyclin-dependent kinase inhibitors, such as p16INK4a, p15INK4b, and p21cip1, were downregulated. Trastuzumab in combination with paclitaxel enhanced antitumor activity in both the sensitive and resistant models. In the trastuzumab-sensitive model, the combination of trastuzumab and paclitaxel resulted in suppression of the AKT–p27kip1–retinoblastoma protein pathway and induction of apoptosis. Although this combination did not suppress retinoblastoma protein phosphorylation in the trastuzumab-resistant model, it did markedly decrease epidermal growth factor receptor and human epidermal growth factor receptor 2 phosphorylation and further enhance paclitaxel-mediated apoptosis. These results suggested that trastuzumab in combination with paclitaxel can still exert more potent antitumor efficacy than each agent alone in trastuzumab-resistant models, providing evidence that trastuzumab remains beneficial in the treatment of trastuzumab-resistant tumors. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.