Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer
| Autor: | Terence M. Williams, Shengyan Xiang, Francisca Beato, Hua Yang, Jose G. Trevino, Jason B. Fleming, Bin Fang, Said M. Sebti, Kazim Husain, Aslamuzzaman Kazi, Mokenge P. Malafa, Liwei Chen, rajanikanth vangipurapu, John M. Koomen, Eric A. Welsh, Patrick W. Underwood |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases Proteome Pancreatic Intraepithelial Neoplasia medicine.disease_cause Article Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences 0302 clinical medicine Cyclin-dependent kinase Pancreatic cancer medicine Animals Humans Phosphorylation neoplasms Cyclin-dependent kinase 1 biology Kinase Phosphoproteomics medicine.disease digestive system diseases Cyclin-Dependent Kinases Pancreatic Neoplasms 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein KRAS Cyclin-dependent kinase 7 |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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