Data from PKC<b>ϵ</b> Is Required for KRAS-Driven Lung Tumorigenesis

Abstract

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 PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Database analysis revealed an association between PKCε expression and poor outcome in patients with lung adenocarcinoma specifically harboring KRAS mutations. A PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-Kras^G12D;PKCε^−/− mice) demonstrated the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which was consistent with impaired transformed growth reported in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout 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 PKCε and KRAS in the control of genes and biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve nonredundant mechanisms. Our results thus, highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.

Significance:

These findings demonstrate that KRAS-mediated tumorigenesis requires PKCε expression and highlight the potential for developing PKCε-targeted therapies for oncogenic RAS-driven malignancies.