Integrated Screens Identify CDK1 as a Therapeutic Target in Advanced Gastrointestinal Stromal Tumors

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