Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

By Jun Liu, Shifeng Pan, Mindy H. Hsieh, Nicholas Ng, Fangxian Sun, Tao Wang, S. Kasibhatla, A. Schuller, Allen G. Li, Dai Cheng and 26 more. 2013

803 citations recorded by the source corpus.

Significance Targeting the Wnt pathway in cancer is an attractive therapeutic approach. However, success has been limited because of the lack of effective therapeutic agents and the lack of biomarkers to define the patient population that would benefit from such a therapy. Herein, we report the discovery of LGK974, a drug that targets Porcupine, a Wnt-specific acyltransferase. We show that LGK974 potently inhibits Wnt signaling, has strong efficacy in rodent tumor models, and is well-tolerated. 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 a strategy and tools for targeting Wnt-driven cancer. 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.

Subfields: Molecular Biology

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Citations in the corpus

An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase Porcupine (2017, background): “High-throughput screening was used to identify GNF-1331, a small molecule that inhibits Wnt secretion in cell-based assays of Wnt signaling and also binds to PORCN-containing membranes (13).”
Wnt addiction of genetically defined cancers reversed by PORCN inhibition (2015, neutral): “21,41 However, given the well established role of Wnts in bone metabolism it will be important to assess the effect of PORCN inhibitors on bone metabolism in clinical studies.”
Integrative clinical genomics of advanced prostate cancer (2015, positive): “Affected individuals s with aberrations in RNF43, ZNRF3, or RSPO2 (overall 6% of affected individuals) are predicted to respond to porcupine inhibitors (Liu et al., 2013).”
In vitro reconstitution of Wnt acylation reveals structural determinants of substrate recognition by the acyltransferase human Porcupine (2018, background): “C59 ( 99% purity) and LGK974 ( 97% purity) inhibitors were purchased from Calbiochem.”
Oral squamous cell carcinomas: state of the field and emerging directions (2023, background): “LGK974 targets PORCN, an acyltransferase vital for producing Wnt proteins in various carcinomas.(403) Targeted drugs hold great potential for OSCC treatments in the clinic.”
Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling (2021, background): “2 M) (PDB: 6TR7) was highlighted due to its structural similarity to the brain hormone melatonin (52) (Figure 14).”
Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours (2021, background): “WNT974 exhibited preclinical activity in multiple tumour models, including Wnt-dependent head and neck cancer and RNF43-mutated pancreatic cancer xenografts.(7,12) Furthermore, dysregulated Wnt signalling has been linked to exclusion of T cells from the tumour microenvironment and resistance to immu”
Wnt/β-catenin signaling in cancers and targeted therapies (2021, background): “Another study showed the incredible use of LGK974 in Rnf43 nonsense mutation cell lines in pancreatic ductal adenocarcinoma (PDAC).124 Both of the two clinical studies illustrated a delayed effect of proliferation inhibition by LGK974.”