Wnt addiction of genetically defined cancers reversed by PORCN inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Enhanced Wnt signaling is a hallmark in certain cancers, often due to mutations affecting Wnt receptors.
• Targeting Wnt secretion, specifically through blocking palmitoleation, presents a potential therapeutic strategy.

Purpose of the Study:

• To develop and evaluate a novel, orally available PORCN inhibitor, ETC-159, for its efficacy in treating Wnt-dependent cancers.
• To investigate the therapeutic potential of inhibiting Wnt secretion in RSPO-translocation bearing colorectal cancer (CRC).

Main Methods:

• Development of ETC-159, a potent and orally available inhibitor of Porcupine O-acyltransferase (PORCN).
• Testing ETC-159 efficacy in patient-derived xenografts of RSPO-translocation bearing colorectal cancer.
• Analysis of transcriptomic changes in RSPO3-translocated cancers following PORCN inhibition.

Main Results:

• ETC-159 demonstrated remarkable effectiveness in treating colorectal cancer patient-derived xenografts with RSPO translocations.
• This represents the first successful targeted therapy for this specific subset of colorectal cancer.
• PORCN inhibition led to significant transcriptomic remodeling, decreasing cell cycle and proliferation genes while increasing differentiation markers.

Conclusions:

• Inhibition of Wnt secretion via PORCN inhibition is a viable therapeutic approach for specific cancer types.
• ETC-159 shows promise as a differentiation therapy for genetically defined human cancers, particularly those with Wnt pathway alterations.