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

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.

In:Nature communications: Springer Science and Business Media LLC12:1, s. 4651-2041-1723

By the author/editor: Ghaddar, N; Wang, S; Woodvine, B; Krishnamoorthy, ...; van Hoef, V; Darini, C; show more...; 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; show less...

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