The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.
Nat Commun
; 12(1): 4651, 2021 07 30.
Article
in En
| MEDLINE
| ID: mdl-34330898
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Adenocarcinoma
/
Eukaryotic Initiation Factor-2
/
Proto-Oncogene Proteins p21(ras)
/
Dual Specificity Phosphatase 6
/
Lung Neoplasms
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2021
Type:
Article
Affiliation country:
Canada