Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma.
Biomarkers, Tumor
/ antagonists & inhibitors
Cell Line, Tumor
Cell Movement
/ genetics
Cell Proliferation
/ genetics
Cystadenocarcinoma, Serous
/ drug therapy
Female
Gene Expression Regulation, Neoplastic
Humans
Mass Spectrometry
/ methods
Molecular Targeted Therapy
/ methods
Myotonin-Protein Kinase
/ antagonists & inhibitors
Neoplasm Grading
Ovarian Neoplasms
/ drug therapy
Protein Kinases
/ genetics
Proteomics
/ methods
RNA Interference
Signal Transduction
/ drug effects
Journal
Science signaling
ISSN: 1937-9145
Titre abrégé: Sci Signal
Pays: United States
ID NLM: 101465400
Informations de publication
Date de publication:
18 02 2020
18 02 2020
Historique:
entrez:
20
2
2020
pubmed:
20
2
2020
medline:
9
2
2021
Statut:
epublish
Résumé
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models. The data revealed a prevalent signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis of these kinases in HGSOC cells indicated MRCKA (also known as CDC42BPA) as a putative therapeutic target. Characterization of the effects of MRCKA knockdown in established HGSOC cell lines demonstrated that MRCKA was integral to signaling that regulated the cell cycle checkpoint, focal adhesion, and actin remodeling, as well as cell migration, proliferation, and survival. Moreover, inhibition of MRCKA using the small-molecule BDP9066 decreased cell proliferation and spheroid formation and induced apoptosis in HGSOC cells, suggesting that MRCKA may be a promising therapeutic target for the treatment of HGSOC.
Identifiants
pubmed: 32071169
pii: 13/619/eaax8238
doi: 10.1126/scisignal.aax8238
pmc: PMC7294993
mid: NIHMS1586611
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Protein Kinases
EC 2.7.-
CDC42BPA protein, human
EC 2.7.1.-
Myotonin-Protein Kinase
EC 2.7.11.1
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
Subventions
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142928
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211670
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009035
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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