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National Institute of Environmental Health Sciences

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Publication Detail

Title: PKCε Is Required for KRAS-Driven Lung Tumorigenesis.

Authors: Garg, Rachana; Cooke, Mariana; Benavides, Fernando; Abba, Martín C; Cicchini, Michelle; Feldser, David M; Kazanietz, Marcelo G

Published In Cancer Res, (2020 12 01)

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-KrasG12D ;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.

PubMed ID: 32994205 Exiting the NIEHS site

MeSH Terms: Adenocarcinoma of Lung/genetics; Adenocarcinoma of Lung/mortality; Adenocarcinoma of Lung/pathology; Animals; Benzo(a)pyrene/toxicity; Carcinoma, Non-Small-Cell Lung/genetics; Carcinoma, Non-Small-Cell Lung/pathology*; Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Lung Neoplasms/chemically induced; Lung Neoplasms/genetics; Lung Neoplasms/mortality; Lung Neoplasms/pathology*; Mice, Knockout; Mice, Transgenic; Mutation; Neoplasms, Experimental/chemically induced; Neoplasms, Experimental/genetics; Protein Kinase C-epsilon/genetics; Protein Kinase C-epsilon/metabolism*; Proto-Oncogene Proteins p21(ras)/genetics*

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