Abstract 1090: Overcoming trastuzumab resistance using trastuzumab deruxtecan (T-DXd), a HER2 targeting antibody drug conjugate, in HER2 amplified gastric cancer

Abstract

Abstract HER2 is amplified in 7% to 20% of gastric cancer (GC) and is associated with poor clinical outcome. Trastuzumab, HER2-targeting antibody, has already been successfully employed for the treatment of HER2 amplified metastatic GC patients. However, most GC patients who achieved an initial response to the trastuzumab-based regimen developed resistance within 1 year after treatment. In this study, we aimed to investigate the efficacy and biological mechanism of trastuzumab deruxtecan (T-DXd) for overcoming trastuzumab resistance in HER2 amplified GC cell lines. We established four trastuzumab resistant cell lines from HER2 amplified GC cell lines by trastuzumab dose-escalation treatment; YCC-33TR, YCC-38TR, NCI-N87TR, and SNU-216TR. Next, we compared the anti-tumor efficacy of trastuzumab and T-DXd (Daiichi Sankyo, Japan), a HER2-targeting antibody-drug conjugate (ADC), in parental and trastuzumab resistant cell lines. Drug sensitivities were determined by the inhibition rates (IR) at 100μg/ml using cell viability assay. Both in baseline and in post-treatment drug responses, expression levels of proteins such as HER2, Erk, Akt, H2A.X and cPARP were detected by western blotting. The parental cell lines were sensitive to trastuzumab, while four trastuzumab resistant (TR) cell lines demonstrated significant resistance to trastuzumab (p<0.05). Compared with the parental cell lines, pHER2 expression was increased in trastuzumab resistant cell lines, and HER2 expression was decreased but still remained at a high level, suggesting that T-DXd can bind to HER2. As expected, T-DXd was sensitive in both parental and trastuzumab resistant cell lines. In detail, sensitivity to T-DXd in parental and resistant cells were as follows: YCC-33 vs YCC-33TR (79.6% vs 90.7%), YCC-38 vs YCC-38TR (94.4% vs 76.5%), NCI-N87 vs NCI-N87TR (83.8% vs 82.6%), and SNU-216 vs SNU-216TR (58.3% vs 42.6%). When treated with T-DXd to trastuzumab resistant cell lines, the expression levels of HER2 and HER2-related molecules showed various patterns for each cell line, and the expression levels of pH2A.X or cPARP were increased compared to trastuzumab treatment. It seems that T-DXd acts to cause DNA damage and induce apoptosis in parental and trastuzumab resistant cell lines. In summary, the established trastuzumab resistant cell lines retained high HER2 expression, and both HER2 amplified parental and trastuzumab resistant cell lines were sensitive to T-DXd. Our data indicated that T-DXd may have a potential therapeutic effect to overcome trastuzumab resistance in GC. Citation Format: Juin Park, Inhye Jeong, Sun Kyoung Kang, Seo Young Yu, Woo Sun Kwon, Tae Soo Kim, Jihyun Hwang, Hyun Cheol Chung, Sun Young Rha. Overcoming trastuzumab resistance using trastuzumab deruxtecan (T-DXd), a HER2 targeting antibody drug conjugate, in HER2 amplified gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1090.