期刊
CLINICAL CANCER RESEARCH
卷 27, 期 14, 页码 4012-4024出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-4781
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类别
资金
- NIH [R01 CA242003, R35 CA197731]
- Joseph & Ann Matella Fund for Pancreatic Cancer Research at the University of Florida
- Proteomics & Metabolomics Core
- Biostatistics and Bioinformatics Core at the H. Lee Moffitt Cancer Center & Research Institute
- NCI-designated Comprehensive Cancer Center [P30 CA076292]
The study revealed that the dependency of pancreatic cancer cells on mutant KRas is driven by the cyclin-dependent kinase (CDK) network, with knocking out CDK targets showing similar effects as knocking out KRas. The CDK inhibitor AT7519 was identified as a potent inducer of apoptosis in mutant KRas-dependent human cancer cells, demonstrating a link between CDK hyperactivation and mutant KRas dependency. This pharmacological approach was shown to effectively inhibit mutant KRas-driven pancreatic cancer in relevant models, suggesting potential for clinical investigations of AT7519 in patients with pancreatic cancer.
Purpose: Among human cancers that harbor mutant (mt) KRas, some, but not all, are dependent on mt KRas. However, little is known about what drives KRas dependency. Experimental Design: Global phosphoproteomics, screening of a chemical library of FDA drugs, and genome-wide CRISPR/Cas9 viability database analysis were used to identify vulnerabilities of KRas dependency. Results: Global phosphoproteomics revealed that KRas dependency is driven by a cyclin-dependent kinase (CDK) network. CRISPR/Cas9 viability database analysis revealed that, in mt KRas-driven pancreatic cancer cells, knocking out the cell-cycle regulators CDK1 or CDK2 or the transcriptional regulators CDK7 or CDK9 was as effective as knocking out KRas. Furthermore, screening of a library of FDA drugs identified AT7519, a CDK1, 2, 7, and 9 inhibitor, as a potent inducer of apoptosis in mt KRas-dependent, but not in mt KRas-independent, human cancer cells. In vivo AT7519 inhibited the phosphorylation of CDK1, 2, 7, and 9 substrates and suppressed growth of xenografts from 5 patients with pancreatic cancer. AT7519 also abrogated mt KRas and mt p53 primary and metastatic pancreatic cancer in three-dimensional (3D) organoids from 2 patients, 3D cocultures from 8 patients, and mouse 3D organoids from pancreatic intraepithelial neoplasia, primary, and metastatic tumors. Conclusions: A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in patients with pancreatic cancer.
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