PKCε Is Required for KRAS-Driven Lung Tumorigenesis
Rachana Garg1, Mariana Cooke1,2, Fernando Benavides3
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Research
|September 30, 2020
Summary
Protein kinase C epsilon (PKCϵ) is essential for KRAS-driven non-small cell lung cancer (NSCLC) development. Targeting PKCϵ offers a potential therapeutic strategy for KRAS-mutated lung adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide.
- Mutant KRAS is a primary driver in lung adenocarcinoma, the most common NSCLC subtype.
- Protein kinase C epsilon (PKCϵ) is an oncogenic kinase implicated in various cancers.
Purpose of the Study:
- To investigate the role of PKCϵ in KRAS-driven lung tumorigenesis.
- To explore the association between PKCϵ expression and patient outcomes in KRAS-mutated lung adenocarcinoma.
- To elucidate the mechanisms underlying PKCϵ's involvement in KRAS-driven NSCLC.
Main Methods:
- Database analysis correlating PKCϵ expression with patient outcomes.
- In vivo studies using genetically engineered mouse models (LSL-Kras;PKCϵ-/- mice).
- In vitro studies with PKCϵ-deficient KRAS-dependent NSCLC cells.
- RNA sequencing for mechanistic analysis.
Main Results:
- PKCϵ expression is associated with poor outcomes in KRAS-mutated lung adenocarcinoma patients.
- PKCϵ is required for KRAS-driven lung tumorigenesis in vivo and transformed growth of NSCLC cells.
- PKCϵ-knockout mice showed reduced susceptibility to carcinogen-induced lung tumors.
- PKCϵ and KRAS regulate distinct sets of genes and pathways in NSCLC.
Conclusions:
- PKCϵ plays a critical, nonredundant role in KRAS-mediated lung tumorigenesis.
- Targeting PKCϵ represents a promising therapeutic strategy for KRAS-driven NSCLC.
- Understanding the interplay between PKCϵ and KRAS can lead to novel cancer treatments.
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