title: Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.
abstract: 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.
authors.affiliation: Genomics Institute of Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Shifeng
authors.initials: S
authors.lastname: Pan
authors.forename: Mindy H
authors.initials: MH
authors.lastname: Hsieh
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ng
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Alwin G
authors.initials: AG
authors.lastname: Schuller
authors.forename: Allen G
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authors.forename: Dai
authors.initials: D
authors.lastname: Cheng
authors.forename: Jie
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authors.lastname: Li
authors.forename: Celin
authors.initials: C
authors.lastname: Tompkins
authors.forename: AnneMarie
authors.initials: A
authors.lastname: Pferdekamper
authors.forename: Auzon
authors.initials: A
authors.lastname: Steffy
authors.forename: Jane
authors.initials: J
authors.lastname: Cheng
authors.forename: Colleen
authors.initials: C
authors.lastname: Kowal
authors.forename: Van
authors.initials: V
authors.lastname: Phung
authors.forename: Guirong
authors.initials: G
authors.lastname: Guo
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Martin P
authors.initials: MP
authors.lastname: Graham
authors.forename: Shannon
authors.initials: S
authors.lastname: Flynn
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Villarroel
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Lilli
authors.initials: L
authors.lastname: Petruzzelli
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Boral
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
authors.forename: Jianwei
authors.initials: J
authors.lastname: Che
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Carey
authors.forename: Gary
authors.initials: G
authors.lastname: Vanasse
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
mesh_terms: D000217:Acyltransferases; D000818:Animals; D060466:Axin Protein / Q000037:antagonists & inhibitors; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D057166:High-Throughput Screening Assays; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D016296:Mutagenesis; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D051381:Rats; D051880:Receptors, Notch / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; D008565:Membrane Proteins; D011719:Pyrazines; D011725:Pyridines; D051880:Receptors, Notch; D000217:Acyltransferases; C491188:PORCN protein, human; C586458:LGK974
keywords: HNSCC; Wnt inhibition; β-catenin