Co-dependency of PKCδ and K-Ras: inverse association with cytotoxic drug sensitivity in KRAS mutant lung cancer

Oncogene. 2017 Jul 27;36(30):4370-4378. doi: 10.1038/onc.2017.27. Epub 2017 Apr 3.


Recent studies suggest that the presence of a KRAS mutation may be insufficient for defining a clinically homogenous molecular group, as many KRAS mutant tumors lose reliance on K-Ras for survival. Identifying pathways that support K-Ras dependency may define clinically relevant KRAS subgroups and lead to the identification of new drug targets. We have analyzed a panel of 17 KRAS mutant lung cancer cell lines classified as K-Ras-dependent or -independent for co-dependency on protein kinase C δ (PKCδ). We show that functional dependency on K-Ras and PKCδ co-segregate, and that dependency correlates with a more epithelial-like phenotype. Furthermore, we show that the pro-apoptotic and pro-tumorigenic functions of PKCδ also segregate based on K-Ras dependency, as K-Ras-independent cells are more sensitive to topoisomerase inhibitors, and depletion of PKCδ in this subgroup suppresses apoptosis through increased activation of extracellular signal-regulated kinase (ERK). In contrast, K-Ras-dependent lung cancer cells are largely insensitive to topoisomerase inhibitors, and depletion of PKCδ can increase apoptosis and decrease activation of ERK in this subgroup. We have previously shown that nuclear translocation of PKCδ is necessary and sufficient for pro-apoptotic signaling. Our current studies show that K-Ras-dependent cells are refractive to PKCδ-driven apoptosis. Analysis of this subgroup showed increased PKCδ expression and an increase in the nuclear:cytoplasmic ratio of PKCδ. In addition, targeting PKCδ to the nucleus induces apoptosis in K-Ras-independent, but not K-Ras-dependent non-small-cell lung cancer (NSCLC) cells. Our studies provide tools for identification of the subset of patients with KRAS mutant tumors most amenable to targeting of the K-Ras pathway, and identify PKCδ as a potential target in this tumor population. These subgroups are likely to be of clinical relevance, as high PKCδ expression correlates with increased overall survival and a more epithelial tumor phenotype in patients with KRAS mutant lung adenocarcinomas.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • DNA Fragmentation
  • Drug Resistance, Neoplasm
  • Gene Knockdown Techniques
  • Humans
  • Immunoblotting
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mutation
  • Protein Kinase C-delta / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Real-Time Polymerase Chain Reaction


  • KRAS protein, human
  • Protein Kinase C-delta
  • Proto-Oncogene Proteins p21(ras)