7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2-3-dihydro-1h-indol-5-yl)-7h-pyrrolo(2-3-d)pyrimidin-4-amine and Carcinogenesis

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.

Topics: Adenine; Adenocarcinoma; Animals; Carcinogenesis; Cell Line, Tumor; Dual Specificity Phosphatase 6; Eukaryotic Initiation Factor-2; Female; Humans; Indoles; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mice, Nude; Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins p21(ras); Stress, Physiological; Xenograft Model Antitumor Assays