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

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 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.