2. Academic Validation
  3. HSP90 inhibitor AUY922 suppresses tumor growth and modulates immune response through YAP1-TEAD pathway inhibition in gastric cancer

HSP90 inhibitor AUY922 suppresses tumor growth and modulates immune response through YAP1-TEAD pathway inhibition in gastric cancer

  • Cancer Lett. 2025 Feb 1:610:217354. doi: 10.1016/j.canlet.2024.217354.
Katsuhiro Yoshimura 1,  Gengyi Zou 2,  Yibo Fan 2,  Kohei Yamashita 2,  Lingzhi Wang 2,  Jingjing Wu 2,  Ruiping Wang 3,  Shan Shao 2,  Ailing W Scott 2,  Jiankang Jin 2,  Melissa Pool Pizzi 2,  Xiaodan Yao 2,  Calena-Abel Brown 2,  Linghua Wang 3,  Qiong Gan 4,  Rebecca E Waters 4,  Feng Yin 4,  Shumei Song 5,  Shilpa S Dhar 6,  Jaffer A Ajani 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Coriell Institute for Medical Research, NJ, USA.
  • 6 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ssdhar@mdanderson.org.
  • 7 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jajani@mdanderson.org.
PMID: 39603381 DOI: 10.1016/j.canlet.2024.217354
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 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.

Keywords

AUY922; Gastric cancer; Heat shock protein 90; TEAD; Tumor immune microenvironment; YAP.

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