Gastrointestinal stromal tumors (GISTs) are the most common type of sarcoma, often driven by mutations in the KIT or PDGFRA genes. Tyrosine kinase inhibitors (TKIs) like imatinib have been the cornerstone of treatment, but most patients eventually develop resistance due to secondary mutations, leading to disease progression and limited survival.
In a study published online in Journal of Experimental Medicine, a research team led by Prof. WANG Yuexiang from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences identified Aurora Kinase B (AURKB) as a critical therapeutic vulnerability in advanced GISTs.
Using an integrated approach including transcriptomic profiling, CRISPR-Cas9 screens, and high-throughput chemical screening, researchers discovered that AURKB was highly overexpressed in high-risk and metastatic GISTs but not in low-risk tumors. This overexpression was driven by transcription factor FOXM1 which directly activates AURKB expression. Genetic knockout of AURKB significantly inhibited tumor growth in vitro and in vivo, inducing cell cycle arrest, senescence and apoptosis.
Moreover, researchers found that AURKB interacts with and stabilizes ATAD2, a protein involved in chromatin remodeling and DNA damage repair. This stabilization occurred through the ubiquitin-proteasome system, and the loss of AURKB led to ATAD2 degradation, impairing tumor proliferation.
Furthermore, researchers 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.
These 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, providing a new treatment strategy for advanced GIST patients.
The study highlights the potential of repurposing AURKB inhibitors, which have already been used in clinical development for other cancers, for use in GISTs. It provides a strong preclinical rationale for pursuing AURKB-directed therapies, and clinical trials will be necessary to validate these findings in humans.
