Abstract 5990: Pertuzumab enhances the antitumor activity of T-DXd in HER2-positive gastric cancer cells

Abstract Simultaneously targeting HER2 and HER3 pathways is a potentially effective strategy for treating patients with HER2-positive gastric cancer (GC). A recent significant advancement in targeted therapy for HER2-positive GC is the development of trastuzumab deruxtecan (T-DXd). However, the co-administration of HER3 blockade with T-DXd to HER2-positive GC has not yet been explored, making this a pioneering study. Our in vitro analysis showed that the cell growth inhibitory effect of T-DXd on HER2-positive GC cells resembled the antiproliferative effect pattern induced by trastuzumab, rather than that caused by DXd. T-DXd reduced the cell viability in a manner closely linked to HER2 expression on the cell membrane. We observed that T-DXd inhibited the phosphorylation of HER3 and, subsequently that of p-AKT S473. The addition of pertuzumab increased T-DXd-induced HER2 internalization and further enhanced its antitumor effect on HER2-positive GC cells, especially when the HER2-HER3 heterodimers are enriched in the cells. By translating our findings into a xenograft model, we showed that combining T-DXd and pertuzumab outperformed single-agent therapy, resulting in significant antitumor effects and apoptosis induction. Our study suggests additional clinical investigations of this new combination strategy using T-DXd and pertuzumab in patients with HER2 positive GC are warranted. Citation Format: Minsu Kang, Kui-Jin Kim, Ji Hea Sung, Milang Nam, Sung-Hyun Hwang, Eun Hee Jung, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Keun-Wook Lee. Pertuzumab enhances the antitumor activity of T-DXd in HER2-positive gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5990.