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...

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Detalles Bibliográficos
Autores principales: Garg, Rachana, Cooke, Mariana, Benavides, Fernando, Abba, Martín Carlos, Cicchini, Michelle, Feldser, David M., Kazanietz, Marcelo G.
Formato: Articulo Preprint
Lenguaje:Inglés
Publicado: 2020
Materias:
Medicina
PKCε
KRAS
carcinogens
mice
lung cancer
Adenocarcinoma
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/128869
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-128869
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Medicina
PKCε
KRAS
carcinogens
mice
lung cancer
Adenocarcinoma
spellingShingle Medicina
PKCε
KRAS
carcinogens
mice
lung cancer
Adenocarcinoma
Garg, Rachana
Cooke, Mariana
Benavides, Fernando
Abba, Martín Carlos
Cicchini, Michelle
Feldser, David M.
Kazanietz, Marcelo G.
PKCε Is Required for KRAS-Driven Lung Tumorigenesis
topic_facet Medicina
PKCε
KRAS
carcinogens
mice
lung cancer
Adenocarcinoma
description 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<sup>G12D</sup>;PKCϵ<sup>-/-</sup> 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.
format Articulo
Preprint
author Garg, Rachana
Cooke, Mariana
Benavides, Fernando
Abba, Martín Carlos
Cicchini, Michelle
Feldser, David M.
Kazanietz, Marcelo G.
author_facet Garg, Rachana
Cooke, Mariana
Benavides, Fernando
Abba, Martín Carlos
Cicchini, Michelle
Feldser, David M.
Kazanietz, Marcelo G.
author_sort Garg, Rachana
title PKCε Is Required for KRAS-Driven Lung Tumorigenesis
title_short PKCε Is Required for KRAS-Driven Lung Tumorigenesis
title_full PKCε Is Required for KRAS-Driven Lung Tumorigenesis
title_fullStr PKCε Is Required for KRAS-Driven Lung Tumorigenesis
title_full_unstemmed PKCε Is Required for KRAS-Driven Lung Tumorigenesis
title_sort pkcε is required for kras-driven lung tumorigenesis
publishDate 2020
url http://sedici.unlp.edu.ar/handle/10915/128869
work_keys_str_mv AT gargrachana pkceisrequiredforkrasdrivenlungtumorigenesis
AT cookemariana pkceisrequiredforkrasdrivenlungtumorigenesis
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AT abbamartincarlos pkceisrequiredforkrasdrivenlungtumorigenesis
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AT feldserdavidm pkceisrequiredforkrasdrivenlungtumorigenesis
AT kazanietzmarcelog pkceisrequiredforkrasdrivenlungtumorigenesis
bdutipo_str Repositorios
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