PMID- 28368426
DCOM- 20170925
LR  - 20180512
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 30
DP  - 2017 Jul 27
TI  - Co-dependency of PKCdelta and K-Ras: inverse association with cytotoxic drug
      sensitivity in KRAS mutant lung cancer.
PG  - 4370-4378
LID - 10.1038/onc.2017.27 [doi]
AB  - 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 (PKCdelta). We show that functional
      dependency on K-Ras and PKCdelta co-segregate, and that dependency correlates
      with a more epithelial-like phenotype. Furthermore, we show that the
      pro-apoptotic and pro-tumorigenic functions of PKCdelta also segregate based on
      K-Ras dependency, as K-Ras-independent cells are more sensitive to topoisomerase 
      inhibitors, and depletion of PKCdelta 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 PKCdelta can increase apoptosis and
      decrease activation of ERK in this subgroup. We have previously shown that
      nuclear translocation of PKCdelta is necessary and sufficient for pro-apoptotic
      signaling. Our current studies show that K-Ras-dependent cells are refractive to 
      PKCdelta-driven apoptosis. Analysis of this subgroup showed increased PKCdelta
      expression and an increase in the nuclear:cytoplasmic ratio of PKCdelta. In
      addition, targeting PKCdelta 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 PKCdelta as a potential target in this tumor population. These subgroups
      are likely to be of clinical relevance, as high PKCdelta expression correlates
      with increased overall survival and a more epithelial tumor phenotype in patients
      with KRAS mutant lung adenocarcinomas.
FAU - Ohm, A M
AU  - Ohm AM
AD  - The Department of Craniofacial Biology, School of Dental Medicine, University of 
      Colorado, Aurora, CO, USA.
FAU - Tan, A-C
AU  - Tan AC
AD  - The Division of Medical Oncology, School of Medicine, University of Colorado,
      Aurora, CO, USA.
FAU - Heasley, L E
AU  - Heasley LE
AD  - The Department of Craniofacial Biology, School of Dental Medicine, University of 
      Colorado, Aurora, CO, USA.
FAU - Reyland, M E
AU  - Reyland ME
AD  - The Department of Craniofacial Biology, School of Dental Medicine, University of 
      Colorado, Aurora, CO, USA.
LA  - eng
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - P50 CA058187/CA/NCI NIH HHS/United States
GR  - R01 DE015648/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170403
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (KRAS protein, human)
RN  - EC (Protein Kinase C-delta)
RN  - EC (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - *Carcinoma, Non-Small-Cell Lung/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - DNA Fragmentation
MH  - Drug Resistance, Neoplasm
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Immunoblotting
MH  - *Lung Neoplasms/genetics/metabolism/pathology
MH  - Mutation
MH  - Protein Kinase C-delta/*metabolism
MH  - Proto-Oncogene Proteins p21(ras)/genetics/*metabolism
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC5532068
MID - NIHMS843069
EDAT- 2017/04/04 06:00
MHDA- 2017/09/26 06:00
CRDT- 2017/04/04 06:00
PHST- 2016/05/20 00:00 [received]
PHST- 2016/12/15 00:00 [revised]
PHST- 2017/01/11 00:00 [accepted]
PHST- 2017/04/04 06:00 [pubmed]
PHST- 2017/09/26 06:00 [medline]
PHST- 2017/04/04 06:00 [entrez]
AID - onc201727 [pii]
AID - 10.1038/onc.2017.27 [doi]
PST - ppublish
SO  - Oncogene. 2017 Jul 27;36(30):4370-4378. doi: 10.1038/onc.2017.27. Epub 2017 Apr