The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.
Adenine
/ analogs & derivatives
Adenocarcinoma
/ drug therapy
Animals
Carcinogenesis
/ drug effects
Cell Line, Tumor
Dual Specificity Phosphatase 6
/ metabolism
Eukaryotic Initiation Factor-2
/ metabolism
Female
Humans
Indoles
/ pharmacology
Kaplan-Meier Estimate
Lung Neoplasms
/ drug therapy
Male
Mice, Nude
Mitogen-Activated Protein Kinases
/ metabolism
Phosphorylation
Proto-Oncogene Proteins p21(ras)
/ genetics
Stress, Physiological
/ genetics
Xenograft Model Antitumor Assays
/ methods
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 07 2021
30 07 2021
Historique:
received:
15
07
2020
accepted:
30
06
2021
entrez:
31
7
2021
pubmed:
1
8
2021
medline:
18
8
2021
Statut:
epublish
Résumé
The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.
Identifiants
pubmed: 34330898
doi: 10.1038/s41467-021-24661-0
pii: 10.1038/s41467-021-24661-0
pmc: PMC8324901
doi:
Substances chimiques
7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
0
Eukaryotic Initiation Factor-2
0
Indoles
0
KRAS protein, human
0
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Dual Specificity Phosphatase 6
EC 3.1.3.48
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Adenine
JAC85A2161
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
4651Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK053307
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK060596
Pays : United States
Informations de copyright
© 2021. The Author(s).
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