Exposure to a number of environmental carcinogens, such as polycyclic aromatic hydrocarbons (PAHs), are the major causative agents of lung cancer, the leading cause of cancer related deaths in the U.S. Oncogenic mutations in KRAS, one of the most common alteration found in non-small cell lung cancer (NSCLC), are induced in high frequency by PAHs and environmental carcinogens. Studies from many laboratories, including ours, established key roles for PKCϵ, a member of the protein kinase C (PKC) family, in mitogenesis and survival of cancer cells. Notably, PKCϵ is up-regulated in several epithelial cancers, including human NSCLC, suggesting a role in the development and/or maintenance of the malignant phenotype. We observed that PKCϵ inhibition/depletion blunt the proliferative, motile, and invasive properties of lung cancer cells with KRAS mutation (PLoS One;7(2):e31714,2012). More importantly, silencing PKCϵ reduced the ability of human NSCLC cells with KRAS mutation to form tumors in nude mice as well as impaired their metastatic potential (Oncogene 31(20):2593-600, 2011). As Ras-transformed cells have enhanced DAG levels and signaling, we hypothesized that genetic targeting of PKCϵ reverses lung tumorigenesis driven by oncogenic Ras. To address this, we intercrossed lung-specific mutant Ras mice (KrasLSL-G12D/+) with PKCϵ knockout mice. Notably, significant inhibition occurred in the formation of lung tumors upon loss of either one or both PKCϵ gene (PRKCE) alleles, with significant extension of mice lifespan, suggesting a role for PKCϵ in the initiation of lung tumorigenesis driven by oncogenic mutant KRas. Furthermore, in silico database analysis of KRAS mutated human lung adenocarcinomas revealed a significant association between high PRKCE expression and poor patient outcome. As environmental lung carcinogens (PAHs) induce mutations in Ras, we next intended to test the hypothesis that PKCϵ is implicated in the action of these carcinogens. Interestingly, alveolar hyperplasia as well as pulmonary adenomas induced by benzo(a)pyrene, a prototypical PAH, were significantly reduced upon loss of one or two PKCϵ alleles, suggesting that genetic ablation of PKCϵ impairs chemically-induced lung carcinogenesis. Overall, our results indicate that PKCϵ is a novel effector of KRAS in lung cancer that may represent a promising target for disease treatment.

Citation Format: Rachana Garg, Veena Kapoor, Martin Abba, David M. Feldser, Steven M. Albelda, Marcelo G. Kazanietz. Protein kinase C epsilon is a mediator of KRAS-driven lung tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5164.