Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 07 2021
15 07 2021
Historique:
received:
10
12
2020
revised:
27
02
2021
accepted:
16
04
2021
pubmed:
22
4
2021
medline:
1
4
2022
entrez:
21
4
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 33879459
pii: 1078-0432.CCR-20-4781
doi: 10.1158/1078-0432.CCR-20-4781
pmc: PMC8493485
mid: NIHMS1697823
doi:
Substances chimiques
KRAS protein, human
0
Proteome
0
Cyclin-Dependent Kinases
EC 2.7.11.22
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4012-4024Subventions
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242003
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197731
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA233444
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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