TY - JOUR
T1 - PKCϵ is required for KRAS-driven lung tumorigenesis
AU - Garg, Rachana
AU - Cooke, Mariana
AU - Benavides, Fernando
AU - Abba, Martín C.
AU - Cicchini, Michelle
AU - Feldser, David M.
AU - Kazanietz, Marcelo G.
N1 - Funding Information:
This work was supported by grants R01-ES026023, R01-CA189765, and R01-CA196232 from the NIH (to M.G. Kazanietz), R01-CA193602 and R01-CA222503 from the NIH and LCD400095 from the American Lung Association (to D.M. Feldser), T32ES019851 from NIH (to M. Cicchini), and PICT-2015-0149 from the Argentine National Agency of Scientific and Technological Promotion (to M.C. Abba). The Laboratory Animal Genetic Services located at MD Anderson Cancer Center was supported by P30 CA16672 DHHS/NCI Cancer Center Support grant (to F. Benavides).
Funding Information:
M. Cicchini reports grants from NIEHS (fellowship funding) during the conduct of the study and personal fees, nonfinancial support, and other compensation from GSK (currently working in Oncology Division of GSK) outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-1300
DO - 10.1158/0008-5472.CAN-20-1300
M3 - Article
C2 - 32994205
AN - SCOPUS:85099293254
SN - 0008-5472
VL - 80
SP - 5166
EP - 5173
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -