Related Experiment Video
Updated: May 8, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Integrated screens identify AURKB dependency in advanced gastrointestinal stromal tumors
Yumei Cheng1, Haoqi Lan1, Xiaojing Lu1
1Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences , Shanghai, China.
Abstract:
The only approved systemic treatments for gastrointestinal stromal tumors (GISTs) are KIT/PDGFRA-directed tyrosine kinase inhibitors (TKIs), which eventually lead to the development of secondary polyclonal resistance mutations. Complementary treatment strategies are urgently needed. Using transcriptomic profiling, CRISPR screens, and chemical screens, we identify aurora kinase B (AURKB) as a previously less recognized therapeutic vulnerability to advanced GISTs. AURKB is frequently overexpressed in high-risk and metastatic GISTs but not in low-/intermediate-risk GISTs across our two patient cohorts, with FOXM1 responsible for AURKB overexpression. Genetic depletion of AURKB inhibits GIST proliferation and growth in vitro and in vivo. Mechanistically, our mass spectrometry-based proteomics screen further reveals that AURKB binds to and stabilizes ATAD2 via the ubiquitin-proteasome system, enhancing chromatin accessibility for DNA damage repair genes. Notably, AURKB inhibitors demonstrate potent efficacy in multiple preclinical GIST cell models and xenograft models at safe doses, overcoming TKI resistance. Our comprehensive approaches define unique AURKB-ATAD2 dependency in GISTs and identify non-receptor tyrosine kinase therapeutic strategies for clinical translation.
Insights
Aurora kinase B (AURKB) is a new therapeutic target for advanced gastrointestinal stromal tumors (GISTs). Inhibiting AURKB shows promise in overcoming tyrosine kinase inhibitor resistance in GIST treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Approved systemic treatments for gastrointestinal stromal tumors (GISTs) include KIT/PDGFRA-directed tyrosine kinase inhibitors (TKIs).
- TKIs eventually lead to secondary polyclonal resistance mutations, necessitating complementary treatment strategies.
Purpose of the Study:
- To identify novel therapeutic vulnerabilities in advanced GISTs beyond current TKI treatments.
- To investigate the role of aurora kinase B (AURKB) as a potential therapeutic target in GIST.
Main Methods:
- Transcriptomic profiling, CRISPR screens, and chemical screens were employed to identify therapeutic targets.
- Mass spectrometry-based proteomics was used to elucidate molecular mechanisms.
- Preclinical GIST cell and xenograft models were utilized to assess therapeutic efficacy.
Main Results:
- Aurora kinase B (AURKB) was identified as a therapeutic vulnerability, frequently overexpressed in high-risk and metastatic GISTs.
- FOXM1 was found to be responsible for AURKB overexpression.
- Genetic depletion of AURKB inhibited GIST proliferation and growth in vitro and in vivo.
- AURKB was shown to bind and stabilize ATAD2, enhancing chromatin accessibility for DNA damage repair genes.
- AURKB inhibitors demonstrated potent efficacy in preclinical models, overcoming TKI resistance at safe doses.
Conclusions:
- A unique AURKB-ATAD2 dependency was defined in GISTs.
- AURKB represents a promising therapeutic target for advanced GISTs, particularly in overcoming TKI resistance.
- Non-receptor tyrosine kinase targeting strategies, specifically involving AURKB, hold potential for clinical translation in GIST treatment.
