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

• 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
• ISSN: 0265-9247; 1521-1878
• DOI: 10.1002/bies.202200026

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.