Yoshimura Katsuhiro, Zou Gengyi, Fan Yibo, Yamashita Kohei, Wang Lingzhi, Wu Jingjing, Wang Ruiping, Shao Shan, Scott Ailing W, Jin Jiankang, Pizzi Melissa Pool, Yao Xiaodan, Brown Calena-Abel, Wang Linghua, Gan Qiong, Waters Rebecca E, Yin Feng, Song Shumei, Dhar Shilpa S, Ajani Jaffer A
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Lett. 2025 Feb 1;610:217354. doi: 10.1016/j.canlet.2024.217354. Epub 2024 Nov 26.
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 invitro and invivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, resulting in down-regulation of target functional genes. AUY922 additionally altered the tumor microenvironment (TME) into an inflamed state with increased cytokine production in T cells, including interferon gamma, granzyme B, and perforin, and inhibited 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. Additionally, our 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.
热休克蛋白90（HSP90）是一种重要的伴侣蛋白，参与多种细胞蛋白的折叠和稳定，调节许多肿瘤细胞的关键功能。在胃腺癌（GAC）中，HSP90的作用在很大程度上仍未得到探索，我们旨在研究HSP90抑制剂AUY922在调节YAP1/TEAD信号通路及其与肿瘤免疫微环境（TME）关联方面的意义。我们的结果表明，AUY922在体外和体内模型中均有效抑制GAC侵袭性，诱导细胞凋亡和细胞周期停滞。各种功能分析表明，AUY922强烈抑制YAP1/TEAD与HSP90之间的表达和相互作用，导致靶功能基因下调。AUY922还将肿瘤微环境（TME）转变为炎症状态，T细胞中细胞因子产生增加，包括干扰素γ、颗粒酶B和穿孔素，并抑制肿瘤相关巨噬细胞的M2极化，使其成为免疫检查点抑制的有利伙伴。我们的研究结果强调了通过下调YAP1/TEAD信号在GAC治疗中靶向HSP90的建议。此外，我们的结果表明，AUY922重塑有利于宿主的GAC TME的能力为结合HSP90和检查点抑制的临床试验奠定了基础，其中HSP90可作为患者选择的生物标志物。
