PMID- 31795447
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210623
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 11
IP  - 12
DP  - 2019 Nov 29
TI  - PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic 
      Neuroendocrine Tumors.
LID - 10.3390/cancers11121902 [doi]
LID - 1902
AB  - Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this 
      study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) 
      and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for 
      PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue 
      compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET 
      cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, 
      PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) 
      suppressed the growth of PNET cell lines and synergized with the mammalian target 
      of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the 
      combination treatment showed down-regulation of known everolimus resistance 
      drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. 
      Metabolomic profiling showed a statistically significant alteration in cellular 
      energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks 
      dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis 
      demonstrated target engagement in vivo and recapitulated in vitro results. Our 
      investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets 
      in the difficult to treat PNET that warrant further clinical investigation.
FAU - Mpilla, Gabriel
AU  - Mpilla G
AUID- ORCID: 0000-0002-0767-015X
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Aboukameel, Amro
AU  - Aboukameel A
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Muqbil, Irfana
AU  - Muqbil I
AD  - University of Detroit Mercy, Detroit, MI 48201, USA.
FAU - Kim, Steve
AU  - Kim S
AUID- ORCID: 0000-0001-9950-1232
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Beydoun, Rafic
AU  - Beydoun R
AD  - Department of Pathology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Philip, Philip A
AU  - Philip PA
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Mohammad, Ramzi M
AU  - Mohammad RM
AUID- ORCID: 0000-0001-8332-5246
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Kamgar, Mandana
AU  - Kamgar M
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Shidham, Vinod
AU  - Shidham V
AD  - Department of Pathology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Senapedis, William
AU  - Senapedis W
AD  - Karyopharm Therapeutics Inc., Newton, MA 02459, USA.
FAU - Baloglu, Erkan
AU  - Baloglu E
AD  - Karyopharm Therapeutics Inc., Newton, MA 02459, USA.
FAU - Li, Jing
AU  - Li J
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Dyson, Gregory
AU  - Dyson G
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Xue, Yue
AU  - Xue Y
AD  - Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
FAU - El-Rayes, Bassel
AU  - El-Rayes B
AD  - Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
FAU - Azmi, Asfar S
AU  - Azmi AS
AUID- ORCID: 0000-0003-1178-9505
AD  - Department of Oncology, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
LA  - eng
GR  - T32 CA009531/CA/NCI NIH HHS/United States
GR  - 1R37CA215427-01A1/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20191129
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC6966587
OTO - NOTNLM
OT  - KPT-9274
OT  - NAMPT
OT  - PAK4
OT  - mTOR
OT  - pancreatic neuroendocrine tumors
COIS- W.S. and E.B. are employed at Karyopharm Therapeutics Inc.
EDAT- 2019/12/05 06:00
MHDA- 2019/12/05 06:01
PMCR- 2019/11/29
CRDT- 2019/12/05 06:00
PHST- 2019/08/12 00:00 [received]
PHST- 2019/11/16 00:00 [revised]
PHST- 2019/11/18 00:00 [accepted]
PHST- 2019/12/05 06:00 [entrez]
PHST- 2019/12/05 06:00 [pubmed]
PHST- 2019/12/05 06:01 [medline]
PHST- 2019/11/29 00:00 [pmc-release]
AID - cancers11121902 [pii]
AID - cancers-11-01902 [pii]
AID - 10.3390/cancers11121902 [doi]
PST - epublish
SO  - Cancers (Basel). 2019 Nov 29;11(12):1902. doi: 10.3390/cancers11121902.