An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Biomarkers, Tumor
/ metabolism
Breast
/ pathology
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm
Eukaryotic Initiation Factor-2
/ metabolism
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Phosphorylation
Prognosis
Receptor, ErbB-2
/ metabolism
Stomach Neoplasms
/ drug therapy
Survival Analysis
Tissue Array Analysis
Trastuzumab
/ pharmacology
Up-Regulation
Xenograft Model Antitumor Assays
eIF-2 Kinase
/ antagonists & inhibitors
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
01
10
2018
accepted:
23
04
2019
entrez:
16
5
2019
pubmed:
16
5
2019
medline:
14
6
2019
Statut:
epublish
Résumé
Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21
Identifiants
pubmed: 31086176
doi: 10.1038/s41467-019-10138-8
pii: 10.1038/s41467-019-10138-8
pmc: PMC6513990
doi:
Substances chimiques
Biomarkers, Tumor
0
Eukaryotic Initiation Factor-2
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
EIF2AK2 protein, human
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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