The Porcupine-selective inhibitor LGK974 safely blocks WNT signaling and tumor growth in vivo.

  • Major finding: The Porcupine-selective inhibitor LGK974 safely blocks WNT signaling and tumor growth in vivo.

  • Clinical relevance: HNSCC cell lines with inactivating NOTCH1 mutations are especially responsive to LGK974.

  • Impact: Porcupine may be a WNT pathway target that can be inhibited while sparing WNT-dependent tissues.

The success of WNT pathway inhibitors has been limited by the narrow therapeutic window afforded by the requirement for WNT signaling in normal tissue homeostasis and the lack of predictive biomarkers of response. By screening over 2 million compounds for the ability to block activation of a WNT-responsive reporter in cells cocultured with WNT-secreting cells, Liu and colleagues identified a hit compound that blocked WNT ligand secretion by specifically binding Porcupine (PORCN), a membrane-bound O-acyltransferase that catalyzes the palmitoylation of WNT ligands. Further optimization led to the development of LGK974, an orally bioavailable PORCN-specific inhibitor that blocked secretion of all canonical WNT ligands tested, inhibited WNT signaling at an IC50 of less than 1 nmol/L in vitro, and led to significant regression of WNT-driven tumors in vivo in association with decreased WNT target gene activation. Importantly, LGK974 was well tolerated in mice and rats without disruption of WNT-dependent tissues, suggesting there might be an appropriate therapeutic window for use of this compound in WNT-driven cancers. The authors screened human cancer cell lines for response to PORCN inhibition and found that LGK974 downregulated WNT target gene expression in 31 of 96 (32%) head and neck squamous cell carcinoma (HNSCC) cell lines and induced tumor regression of an HSNCC xenograft. Exome sequencing of HNSCC cell lines revealed an enrichment of inactivating NOTCH1 mutations in LGK974-responsive cell lines. Given that NOTCH has been shown to suppress WNT signaling in multiple contexts, these findings raise the possibility that increased WNT pathway activation caused by loss of NOTCH signaling may confer sensitivity to WNT inhibitors. Together, these findings show that PORCN inhibition can safely induce regression of WNT-dependent tumors in vivo and identify a potential patient population that might benefit from this therapeutic strategy.

Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, et al. Targeting Wnt-driven cancer through inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A 2013 Nov 25 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013