PKC ε Is Required for KRAS-Driven Lung Tumorigenesis

GARG, RACHANA; COOKE, MARIANA; BENAVIDES, FERNANDO; ABBA, MARTÍN C.; CICCHINI, MICHELLE; FELDSER, DAVID M.; KAZANIETZ, MARCELO G.

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2020 vol. 80 p. 5166 - 5173

0008-5472

Non?small cell lung cancer (NSCLC) is the most frequentsubtype of lung cancer and remains a highly lethal malignancy andone of the leading causes of cancer-related deaths worldwide.Mutant KRAS is the prevailing oncogenic driver of lung adenocar-cinoma, the most common histologic form of NSCLC. In this study,we examined the role of PKCe, an oncogenic kinase highlyexpressed in NSCLC and other cancers, in KRAS-driven tumori-genesis. Database analysis revealed an association between PKCeexpression and poor outcome in patients with lung adenocarcinomaspecifically harboring KRAS mutations. A PKCe-deficient, condi-tionally activatable allele of oncogenic Kras (LSL-Kras G12D ;PKCe / mice) demonstrated the requirement of PKCe forKras-driven lung tumorigenesis in vivo, which was consistentwith impaired transformed growth reported in PKCe-deficient KRAS-dependent NSCLC cells. Moreover, PKCe-knockout micewere found to be less susceptible to lung tumorigenesis induced bybenzo[a]pyrene, a carcinogen that induces mutations in Kras.Mechanistic analysis using RNA sequencing revealed little overlapfor PKCe and KRAS in the control of genes and biological pathwaysrelevant in NSCLC, suggesting that a permissive role of PKCe inKRAS-driven lung tumorigenesis may involve nonredundantmechanisms. Our results thus, highlight the relevance and potentialof targeting PKCe for lung cancer therapeutics.