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

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 headand neck cancercell lines with loss-of-function mutations in the Notch signaling pathwayhave a high response rate to LGK974. Together, these findings provide a strategy and tools for targeting Wnt-driven cancer.