Mechanistic schematic of AURKB as a therapeutic goal in superior GIST. Credit score: Prof. Wang Yuexiang’s group
Gastrointestinal stromal tumors (GISTs) are the most typical sort of sarcoma, typically pushed by mutations within the KIT or PDGFRA genes. Tyrosine kinase inhibitors (TKIs) like imatinib have been the cornerstone of therapy, however most sufferers ultimately develop resistance resulting from secondary mutations, resulting in illness development and restricted survival.
In a examine printed on-line within the Journal of Experimental Medication, a analysis staff led by Prof. Wang Yuexiang from the Shanghai Institute of Vitamin and Well being of the Chinese language Academy of Sciences recognized Aurora Kinase B (AURKB) as a essential therapeutic vulnerability in superior GISTs.
Utilizing an built-in method together with transcriptomic profiling, CRISPR-Cas9 screens, and high-throughput chemical screening, researchers found that AURKB was extremely overexpressed in high-risk and metastatic GISTs however not in low-risk tumors.
This overexpression was pushed by transcription issue FOXM1, which straight prompts AURKB expression. Genetic knockout of AURKB considerably inhibited tumor development in vitro and in vivo, inducing cell cycle arrest, senescence and apoptosis.
Furthermore, researchers discovered that AURKB interacts with and stabilizes ATAD2, a protein concerned in chromatin transforming and DNA injury restore. This stabilization occurred by the ubiquitin-proteasome system, and the lack of AURKB led to ATAD2 degradation, impairing tumor proliferation.
The researchers demonstrated that AURKB inhibitors, resembling AZD1152, successfully suppressed tumor development in a number of preclinical fashions, together with patient-derived xenografts immune to first- by fourth-line TKIs. These inhibitors had been well-tolerated with no important toxicity noticed in animal fashions.
These findings reveal a beforehand unrecognized AURKB-ATAD2 axis that’s particular to GISTs and represents a promising therapeutic goal. Focusing on AURKB might overcome TKI resistance, offering a brand new therapy technique for superior GIST sufferers.
The examine highlights the potential of repurposing AURKB inhibitors, which have already been utilized in scientific growth for different cancers, to be used in GISTs. It gives a powerful preclinical rationale for pursuing AURKB-directed therapies, and scientific trials will likely be essential to validate these findings in people.
Extra info:
Yumei Cheng et al, Built-in screens determine AURKB dependency in superior gastrointestinal stromal tumors, Journal of Experimental Medication (2025). DOI: 10.1084/jem.20250256
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Chinese language Academy of Sciences
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Researchers determine new therapeutic goal in superior gastrointestinal stromal tumors (2025, August 27)
retrieved 28 August 2025
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