Wnt addiction of genetically defined cancers reversed by PORCN inhibition

摘要: Enhanced sensitivity to Wnts is an emerging hallmark of a subset cancers, defined in part by mutations regulating the abundance their receptors. Whether these identify clinical opportunity important question. Inhibition Wnt secretion blocking essential post-translational modification, palmitoleation, provides useful therapeutic intervention. We developed novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks and activity all Wnts. ETC-159 remarkably effective treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This first example targeted therapy for this CRC. Consistent with central role signaling regulation gene expression, inhibition RSPO3-translocated cancers causes marked remodeling transcriptome, loss cell cycle, stem proliferation genes, increase differentiation markers. holds promise as genetically human cancers.