Requirement for PKC epsilon in KRAS-driven lung tumorigenesis

Abstract

Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCepsilon, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCepsilon expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCepsilon-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCepsilon-/- mice) we were able to demonstrate the requirement of PKCepsilon for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCepsilon-deficient KRAS-dependent NSCLC cells. Moreover, PKCepsilon-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-Seq revealed little overlapping for PKCepsilon and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCepsilon in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCepsilon for lung cancer therapeutics.