Integrated Screens Identify Cdk1 As A Therapeutic Target In Advanced Gastrointestinal Stromal Tumors

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry- based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials.Significance: These findings propose CDK1 as a novel cell-cycle-independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.