Abstract 517: YAP-TEAD-mediated tumor suppression and immune modulation of gastric adenocarcinoma by HSP90 inhibition

Abstract Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the in-vitro and in-vivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, evoking in down-regulation of target functional genes. AUY922 additionally altered the TME into an inflamed state with increased cytokine production in T-cells and inhibition of M2-polarization of tumor-associated macrophages, rendering it a favorable partner for immune checkpoint inhibition. Our findings highlighted the suggestion of targeting HSP90 in GAC therapy via down-regulating YAP1/TEAD signaling. Further, results suggest that AUY922's ability to reshape the GAC TME favoring the host sets the stage for a clinical trial that combines HSP90 and checkpoint inhibition, where HSP90 could serve as a biomarker for patient selection. Citation Format: Katsuhiro Yoshimura, Gengyi Zou, Yibo Fan, Kohei Yamashita, Jingjing Wu, Ruiping Wang, Shan Shao, Ailing Scott, Jiankang Jin, Melissa Pizzi, Xiaodan Yao, Calena Brown, Lingzhi Wang, Linghua Wang, Qiong Gan, Rebecca Waters, Yin Feng, Shumei Song, Shilpa Dhar, Jaffer Ajani. YAP-TEAD-mediated tumor suppression and immune modulation of gastric adenocarcinoma by HSP90 inhibition [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 517.