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

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 delta (PKC delta). We show that functional dependency on K-Ras and PKC delta co-segregate, and that dependency correlates with a more epithelial-like phenotype. Furthermore, we show that the pro-apoptotic and pro-tumorigenic functions of PKC delta also segregate based on K-Ras dependency, as K-Ras-independent cells are more sensitive to topoisomerase inhibitors, and depletion of PKC delta 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 PKC delta can increase apoptosis and decrease activation of ERK in this subgroup. We have previously shown that nuclear translocation of PKC delta is necessary and sufficient for proapoptotic signaling. Our current studies show that K-Ras-dependent cells are refractive to PKC delta-driven apoptosis. Analysis of this subgroup showed increased PKC delta expression and an increase in the nuclear: cytoplasmic ratio of PKC delta. In addition, targeting PKCd 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 PKC delta as a potential target in this tumor population. These subgroups are likely to be of clinical relevance, as high PKC delta expression correlates with increased overall survival and a more epithelial tumor phenotype in patients with KRAS mutant lung adenocarcinomas.