dataset posted on 2023-03-31, 04:47 authored by Xiaojing Lu, Yuzhi Pang, Hui Cao, Xiaoxiao Liu, Lin Tu, Yanying Shen, Xiaona Jia, Jen-Chieh Lee, Yuexiang Wang
Supplementary Tables 1-5. Supplementary Table S1. Clinicopathologic classification and CDK1 expression for the discovery GIST cohort (n=43). Supplementary Table S2: List of all 14280 genes expressed in GIST. Supplementary Table S3: List of 568 genes with a higher expression level in advanced GIST than in early-stage GIST. Supplementary Table S4: Ranked CRISPR scores for each gene from a genome-wide CRISPR screen in GIST430/654 cells. Supplementary Table S5: Clinicopathologic classification and CDK1 expression for the validation GIST cohort (n=92).
National Natural Science Foundation of China
National Key R&D Program of China
Shanghai Science and Technology Commission
Tissue Microenvironment and Tumor of Chinese Academy of Sciences
Brigham and Women's Hospital
ARTICLE ABSTRACTOncogenic 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.
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.