Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ghaddar, N; Wang, S; Woodvine, B; Krishnamoorthy, J; van Hoef, V; Darini, C; Kazimierczak, U; Ah-son, N; Popper, H; Johnson, M; Officer, L; Teodosio, A; Broggini, M; Mann, KK; Hatzoglou, M; Topisirovic, I; Larsson, O; Le Quesne, J; Koromilas, AE.
The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer
NAT COMMUN. 2021; 12(1): 4651
Doi: 10.1038/s41467-021-24661-0
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- Co-Autor*innen der Med Uni Graz
- Popper Helmuth
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- 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-eIF2 alpha), 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-eIF2 alpha 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. The Integrated Stress Response (ISR) is a cytoprotective pathway upregulated in many cancers. Here the authors show that the activation of PERK/p-eIF2 alpha arm of ISR enhances ERK phosphorylation through translation repression of DUSP6, thus resulting in KRAS-driven lung tumorigenesis.