The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer
Nour Ghaddar, Shuo Wang, Bethany Woodvine, Jothilatha Krishnamoorthy, Vincent van Hoef, Cédric Darini, Urszula Kazimierczak, Nicolas Ah-son, Helmuth Popper, Myriam Johnson, Leah Officer-Jones, Ana Teodòsio, Massimo Broggini, Koren K. Mann, Maria Hatzoglou, Ivan Topisirović, Ola Larsson, John Le Quesne, Antonis E. Koromilas
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.