PKCε Is Required for KRAS-Driven Lung Tumorigenesis.

Non-small cell lung cancer (NSCLC) is the most frequent subtype of lung cancer and remains a highly lethal malignancy and one of the leading causes of cancer-related deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histologic form of NSCLC. In this study, we examined the role of an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Database analysis revealed an association between expression and poor outcome in patients with lung adenocarcinoma specifically harboring KRAS mutations. A conditionally activatable allele of oncogenic Kras (LSL-Kras mice) demonstrated the requirement of duanyu1531ϵ for Kras-driven lung tumorigenesis in vivo, which was consistent with impaired transformed growth reported in KRAS-dependent NSCLC cells. Moreover, mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA sequencing revealed little overlap for duanyu1531ϵ and KRAS in the control of genes and biological pathways relevant in NSCLC, suggesting that a permissive role of duanyu1531ϵ in KRAS-driven lung tumorigenesis may involve nonredundant mechanisms. Our results thus, highlight the relevance and potential of targeting duanyu1531ϵ for lung cancer therapeutics. SIGNIFICANCE: These findings demonstrate that KRAS-mediated tumorigenesis requires duanyu1531ϵ expression and highlight the potential for developing therapies for oncogenic RAS-driven malignancies.

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