The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

Ghaddar, N. et al. (2021) The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer. Nature Communications, 12, 4651. (doi: 10.1038/s41467-021-24661-0) (PMID:34330898) (PMCID:PMC8324901)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Le Quesne, Professor John
• Authors: Ghaddar, N., Wang, S., Woodvine, B., Krishnamoorthy, J., van Hoef, V., Darini, C., Kazimierczak, U., Ah-son, N., Popper, H., Johnson, M., Officer, L., Teodósio, A., Broggini, M., Mann, K. K., Hatzoglou, M., Topisirovic, I., Larsson, O., Le Quesne, J., and Koromilas, A. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 4651
• Publisher Policy: Reproduced under a Creative Commons License