PMID- 24277854
OWN - NLM
STAT- MEDLINE
DCOM- 20140221
LR  - 20231120
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 50
DP  - 2013 Dec 10
TI  - Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.
PG  - 20224-9
LID - 10.1073/pnas.1314239110 [doi]
AB  - Wnt signaling is one of the key oncogenic pathways in multiple cancers, and 
      targeting this pathway is an attractive therapeutic approach. However, 
      therapeutic success has been limited because of the lack of therapeutic agents 
      for targets in the Wnt pathway and the lack of a defined patient population that 
      would be sensitive to a Wnt inhibitor. We developed a screen for small molecules 
      that block Wnt secretion. This effort led to the discovery of LGK974, a potent 
      and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a 
      membrane-bound O-acyltransferase that is required for and dedicated to 
      palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand 
      secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in 
      vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the 
      expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious 
      in multiple tumor models at well-tolerated doses in vivo, including murine and 
      rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and 
      neck squamous cell carcinoma model (HN30). We also show that head and neck cancer 
      cell lines with loss-of-function mutations in the Notch signaling pathway have a 
      high response rate to LGK974. Together, these findings provide both a strategy 
      and tools for targeting Wnt-driven cancers through the inhibition of PORCN.
FAU - Liu, Jun
AU  - Liu J
AD  - Genomics Institute of Novartis Research Foundation, San Diego, CA 92121.
FAU - Pan, Shifeng
AU  - Pan S
FAU - Hsieh, Mindy H
AU  - Hsieh MH
FAU - Ng, Nicholas
AU  - Ng N
FAU - Sun, Fangxian
AU  - Sun F
FAU - Wang, Tao
AU  - Wang T
FAU - Kasibhatla, Shailaja
AU  - Kasibhatla S
FAU - Schuller, Alwin G
AU  - Schuller AG
FAU - Li, Allen G
AU  - Li AG
FAU - Cheng, Dai
AU  - Cheng D
FAU - Li, Jie
AU  - Li J
FAU - Tompkins, Celin
AU  - Tompkins C
FAU - Pferdekamper, AnneMarie
AU  - Pferdekamper A
FAU - Steffy, Auzon
AU  - Steffy A
FAU - Cheng, Jane
AU  - Cheng J
FAU - Kowal, Colleen
AU  - Kowal C
FAU - Phung, Van
AU  - Phung V
FAU - Guo, Guirong
AU  - Guo G
FAU - Wang, Yan
AU  - Wang Y
FAU - Graham, Martin P
AU  - Graham MP
FAU - Flynn, Shannon
AU  - Flynn S
FAU - Brenner, J Chad
AU  - Brenner JC
FAU - Li, Chun
AU  - Li C
FAU - Villarroel, M Cristina
AU  - Villarroel MC
FAU - Schultz, Peter G
AU  - Schultz PG
FAU - Wu, Xu
AU  - Wu X
FAU - McNamara, Peter
AU  - McNamara P
FAU - Sellers, William R
AU  - Sellers WR
FAU - Petruzzelli, Lilli
AU  - Petruzzelli L
FAU - Boral, Anthony L
AU  - Boral AL
FAU - Seidel, H Martin
AU  - Seidel HM
FAU - McLaughlin, Margaret E
AU  - McLaughlin ME
FAU - Che, Jianwei
AU  - Che J
FAU - Carey, Thomas E
AU  - Carey TE
FAU - Vanasse, Gary
AU  - Vanasse G
FAU - Harris, Jennifer L
AU  - Harris JL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131125
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (AXIN2 protein, human)
RN  - 0 (Axin Protein)
RN  - 0 (Membrane Proteins)
RN  - 0 (Pyrazines)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, Notch)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (PORCN protein, human)
RN  - U27F40013Q (LGK974)
SB  - IM
MH  - Acyltransferases
MH  - Animals
MH  - Axin Protein/antagonists & inhibitors
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cloning, Molecular
MH  - High-Throughput Screening Assays
MH  - Humans
MH  - Membrane Proteins/*antagonists & inhibitors
MH  - Mice
MH  - Mutagenesis
MH  - Neoplasms/*drug therapy
MH  - Phosphorylation/drug effects
MH  - Pyrazines/*pharmacology/therapeutic use
MH  - Pyridines/*pharmacology/therapeutic use
MH  - Radioligand Assay
MH  - Rats
MH  - Receptors, Notch/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Wnt Signaling Pathway/*drug effects
PMC - PMC3864356
OTO - NOTNLM
OT  - HNSCC
OT  - Wnt inhibition
OT  - beta-catenin
COIS- Conflict of interest statement: J. Liu, S.P., M.H.H., N.N., T.W., S.K., D.C., J. 
      Li, C.T., A.P., A.S., C.K., Y.W., C.L., P.M., W.R.S., L.P., A.L.B., H.M.S., 
      M.E.M., J. Che, G.V., and J.L.H. are employees of Novartis.
EDAT- 2013/11/28 06:00
MHDA- 2014/02/22 06:00
PMCR- 2014/06/10
CRDT- 2013/11/27 06:00
PHST- 2013/11/27 06:00 [entrez]
PHST- 2013/11/28 06:00 [pubmed]
PHST- 2014/02/22 06:00 [medline]
PHST- 2014/06/10 00:00 [pmc-release]
AID - 1314239110 [pii]
AID - 201314239 [pii]
AID - 10.1073/pnas.1314239110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. doi: 
      10.1073/pnas.1314239110. Epub 2013 Nov 25.