The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. This study demonstrates that ISR is pivotal in lung adenocarcinoma (LUAD) development. Increased phosphorylation of the translation initiation factor eIF2α (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, substantially reduce tumor growth and prolong mouse survival, providing a potential therapeutic option for KRAS-driven lung cancer. These data provide a rationale for ISR-based regimens in LUAD treatment.

Nour Ghaddar, Shuo Wang, Bethany Woodvine, Jothilatha Krishnamoorthy, Vincent van Hoef, Cedric Darini, Urszula Kazimierczak, Nicolas Ah-son, Helmuth Popper, Myriam Johnson, Leah Officer, Ana Teodósio, Massimo Broggini, Koren K. Mann, Maria Hatzoglou, Ivan Topisirovic, Ola Larsson, John Le Quesne, Antonis E. Koromilas