The integrated stress response in the induction of mutant KRAS lung carcinogenesis: Mechanistic insights and therapeutic implications

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogram...

Full description

Saved in:
Bibliographic Details
Published in:BioEssays 2022-08, Vol.44 (8), p.e2200026-n/a
Main Author: Koromilas, Antonis E.
Format: Article
Language:English
Subjects:
cancer therapeutics
Carcinogenesis
Carcinogens
Gene expression
Genotoxicity
Immunological tolerance
K-Ras protein
KRAS oncogene
lung adenocarcinoma
Lungs
mRNA translation
Mutation
oncogenic stress
Phosphorylation
Regulatory mechanisms (biology)
transgenic mouse
Translation
translation initiation factor eIF2
Tumorigenesis
Tumors
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. KRAS mutations elicit oncogenic stress causing the upregulation of adaptive ISR, which employs activated PERK and increased eIF2α phosphorylation (eIF2α‐P) to stimulate lung tumorigenesis. ISR inhibitors exhibit anti‐tumor effects in mutant KRAS lung cancers. The PERK‐eIF2α‐P arm acts via autonomous and immune mediated mechanisms to promote tumor growth and chemoresistance.
ISSN:0265-9247
1521-1878
DOI:10.1002/bies.202200026