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 Wntdriven cancers through the inhibition of PORCN.Wnt inhibition | β-catenin | HNSCC

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

“…Inhibition of Notch signaling increases the expression of Wnt ligands, leading to increased Wnt signaling (59). Consistent with this, loss-of-function mutations in Notch1 in head and neck squamous cell carcinoma cell lines sensitize them to PORCN inhibitors (34). Loss-of-function mutations in Notch1 are found in diverse epithelial cancers.…”

“…Consistent with this, tankyrase inhibitors demonstrated severe, mechanism-based GI toxicity when given orally (14). In contrast with tankyrase inhibitors, PORCN inhibitors and the recombinant Frizzled inhibitory antibodies have not shown significant toxic effects on the intestine or skin, at least in mice, at doses that effectively inhibit cancer proliferation (30,34,37). Doses of the PORCN inhibitor Wnt C-59 10-fold higher than the therapeutic dose cause extensive loss of intestinal proliferation (37).…”

ERAD‐dependent control of the Wnt secretory factor Evi

“…A better understanding of the mechanisms underlying Wnt signaling therefore might lay the foundation for novel therapeutic approaches. Blocking Wnt secretion with the Porcn inhibitor LGK974 induced regression of multiple tumor models in vivo (Liu et al , 2013) and is currently being investigated in clinical studies (Lum & Chen, 2015; Zhan et al , 2017). Despite the high relevance of secreted Wnt ligands in different cancers and the reported additional Wnt‐independent functions of Porcn (Covey et al , 2012; Erlenhardt et al , 2016), inhibition of Porcn is to date the only pharmacological approach to inhibit Wnt secretion.…”

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

“…Epigenetic inactivation of WNT signaling antagonists such as the SFRP genes is not restricted to cSCC, but rather is detected in a variety of other types of SCC tumours, including oral (Paluszczak, et al 2015;Pannone, et al 2010;Sogabe, et al 2008), oesphageal (Kishino, et al 2016;Liu, et al 2011;Meng, et al 2011;Saito, et al 2014;Yang, et al 2012), cervical (Delmas, et al 2011;Siegel, et al 2015) and head & neck (HN) SCCs (Marsit, et al 2006), and thus could represent a universal mechanism of WNT activation in SCC tumours. LGK974, is well-tollerated, potent and highly efficatious in human HNSCC cells (Liu, et al 2013), suggesting it may prove a lead therapeutic in other SCCs where WNT/β-catenin signaling drives carcinogenesis. Consistent with this is the interesting finding that another Porcupine inhibitor, IWP2, can induce tumour regression in chemically induced murine keratoacanthomas (a HF-derived benign variant of cSCC), which highlights WNT/β-catenin signaling as a key regulator to sustain cutaneous tumour growth (Zito, et al 2014).…”

“…For example, the identification that a loss of Notch in cSCC results in activation of β-catenin signaling, suggests that cSCC patients with Notch loss-of-function mutations may benefit from intervention with WNT/β-catenin pathway inhibitors. Consistant with this hypothesis, is the finding that loss of Notch1 activity in HNSCC cells correlates with LGK974 responsiveness (Liu, et al 2013).…”