Maria Hatzoglou, Cedric Darini, Nour Ghaddar, John Le Quesne, Myriam Johnson, Ola Larsson, Leah Officer, Antonis E. Koromilas, Jothilatha Krishnamoorthy, Bethany Woodvine, Shuo Wang, Koren K. Mann, Vincent van Hoef, H. Popper, Massimo Broggini, Ivan Topisirovic, Ana Teodósio, Urszula Kazimierczak, Nicolas Ah-son, Woodvine, Bethany [0000-0001-8359-6476], Popper, Helmuth [0000-0003-4970-1265], Officer, Leah [0000-0002-3690-2386], Teodósio, Ana [0000-0002-1386-6730], Broggini, Massimo [0000-0002-8138-9358], Hatzoglou, Maria [0000-0003-2037-1231], Topisirovic, Ivan [0000-0002-5510-9762], Larsson, Ola [0000-0003-1412-1308], Le Quesne, John [0000-0003-3552-7446], Koromilas, Antonis E [0000-0003-1972-0799], Apollo - University of Cambridge Repository, and Koromilas, Antonis E. [0000-0003-1972-0799]
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., The Integrated Stress Response (ISR) is a cytoprotective pathway upregulated in many cancers. Here the authors show that the activation of PERK/p-eIF2α arm of ISR enhances ERK phosphorylation through translation repression of DUSP6, thus resulting in KRAS-driven lung tumorigenesis.