Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition.
DNA damage response
immuno-MRM
multiple reaction monitoring
targeted proteomics
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
30 Jul 2021
30 Jul 2021
Historique:
received:
18
06
2021
revised:
20
07
2021
accepted:
23
07
2021
entrez:
7
8
2021
pubmed:
8
8
2021
medline:
8
8
2021
Statut:
epublish
Résumé
The ATM serine/threonine kinase (HGNC: ATM) is involved in initiation of repair of DNA double-stranded breaks, and ATM inhibitors are currently being tested as anti-cancer agents in clinical trials, where pharmacodynamic (PD) assays are crucial to help guide dose and scheduling and support mechanism of action studies. To identify and quantify PD biomarkers of ATM inhibition, we developed and analytically validated a 51-plex assay (DDR-2) quantifying protein expression and DNA damage-responsive phosphorylation. The median lower limit of quantification was 1.28 fmol, the linear range was over 3 orders of magnitude, the median inter-assay variability was 11% CV, and 86% of peptides were stable for storage prior to analysis. Use of the assay was demonstrated to quantify signaling following ionizing radiation-induced DNA damage in both immortalized lymphoblast cell lines and primary human peripheral blood mononuclear cells, identifying PD biomarkers for ATM inhibition to support preclinical and clinical studies.
Identifiants
pubmed: 34359745
pii: cancers13153843
doi: 10.3390/cancers13153843
pmc: PMC8345163
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : U24 CA160034
Pays : United States
Organisme : NCI NIH HHS
ID : R50CA211499
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211499
Pays : United States
Organisme : NCI NIH HHS
ID : U24CA160034
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214114
Pays : United States
Organisme : NCI NIH HHS
ID : U01CA214114
Pays : United States
Organisme : Office of Research Infrastructure Programs, National Institutes of Health
ID : S10OD028685
Organisme : NCI NIH HHS
ID : R01CA235575
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA235575
Pays : United States
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