A research article describing Aurora Kinase B (AURKB) as a critical therapeutic vulnerability in advanced gastrointestinal stromal tumors (GISTs), entitled “Integrated Screens Identify AURKB Dependency in Advanced Gastrointestinal Stromal Tumors”, was published online in the scientific journal Journal of Experimental Medicine on August 25, 2025.

GISTs are the most common type of sarcoma, often driven by mutations in the KIT or PDGFRA genes. While tyrosine kinase inhibitors (TKIs) like imatinib have been the cornerstone of treatment, most patients eventually develop resistance due to secondary mutations, leading to disease progression and limited survival.

Using an integrated approach that included transcriptomic profiling, CRISPR-Cas9 screens, and high-throughput chemical screening, the research team led by Prof. WANG Yuexiang from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, discovered that AURKB is highly overexpressed in high-risk and metastatic GISTs but not in low-risk tumors. This overexpression is driven by the transcription factor FOXM1, which directly activates AURKB expression. Genetic knockout of AURKB significantly inhibited tumor growth both in vitro and in vivo, inducing cell cycle arrest, senescence, and apoptosis.

Importantly, the team found that AURKB interacts with and stabilizes ATAD2, a protein involved in chromatin remodeling and DNA damage repair. This stabilization occurs through the ubiquitin-proteasome system, and loss of AURKB led to ATAD2 degradation, impairing tumor proliferation.

The study also demonstrated that AURKB inhibitors, such as AZD1152, effectively suppressed tumor growth in multiple preclinical models, including patient-derived xenografts resistant to first- through fourth-line TKIs. These inhibitors were well-tolerated, with no significant toxicity observed in animal models.

The findings reveal a previously unrecognized AURKB-ATAD2 axis that is specific to GISTs and represents a promising therapeutic target. Targeting AURKB could overcome TKI resistance and provide a new treatment strategy for advanced GIST patients, particularly those resistant to standard treatments. The research highlights the potential of repurposing AURKB inhibitors, already in clinical development for other cancers, for use in GISTs. Clinical trials will be necessary to validate these findings in humans, but the study provides a strong preclinical rationale for pursuing AURKB-directed therapies.

The research was supported by Prof. WANG Ming and Prof. CAO Hui from the Renji Hospital. This project was financially supported by grants from the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Oriental Talent Program (Shanghai Academic Research Leader Program) and other funding agencies, underscoring the importance of collaborative and multidisciplinary efforts in advancing cancer research.

Mechanistic schematic of AURKB as a therapeutic target in advanced GIST. (Image provided Prof. WANG Yuexiang’s group)

Paper link: https://doi.org/10.1084/jem.20250256

Scientific Contact:
Prof. WANG Yuexiang
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: yxwang76@sinh.ac.cn 

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn