Abstract C01: Porcupine inhibition redirects mitochondrial metabolism in Wnt-dependent pancreatic cancer

Abstract

Abstract Wnt/β-catenin signaling plays important roles in pancreatic ductal adenocarcinoma (PDA) tumor initiation and progression via broad-ranging effects on proliferation, differentiation, survival, and stemness. Although Wnt has been shown to promote glycolysis in colon cancer, its role in regulating metabolism in PDA has not been well explored. For this study, RNF43-mutant cell lines were selected as exemplars of ligand-dependent autocrine Wnt signaling in PDA. These cell lines harbor an inactivating mutation in RNF43 that confers Wnt growth-dependency and response to LGK974, a PORCN inhibitor that blocks Wnt ligand secretion and signaling. Global transcriptomic, proteomic, and metabolomic analysis revealed several metabolites and putative mediators of metabolism that are directly or indirectly linked to autocrine Wnt signaling. Pharmacologic inhibition of Wnt by LGK974 led to the accumulation of pyruvate and lactate, as well as reduced tricarboxylic acid cycle metabolites and decreased mitochondrial membrane potential as measured by tetramethylrhodamine and JC-1 assays. These metabolic changes were accompanied by cell cycle arrest and downregulation of transcriptional programs involved in cell cycle progression, DNA replication, and nucleotide metabolism. Importantly, LGK974 results were phenocopied by siRNA-mediated knockdown of WNT7B and rescued with WNT3A conditioned media. Thus, inhibition of mitochondrial oxidative phosphorylation by LGK974 in RNF43-mutant PDA appears linked to its inhibition of canonical Wnt signaling, an adaptation and potential metabolic vulnerability that could be leveraged to therapeutic advantage via combinatorial strategies. Altogether, these results suggest tissue context and mechanisms of Wnt pathway activation may profoundly influence its role in regulating cancer metabolism. Citation Format: Kristina Y. Aguilera, Rana Riahi, Edris A. Saadat, Anna R. Lay, Thuc Le, Timothy R. Donahue, Caius Radu, David W. Dawson. Porcupine inhibition redirects mitochondrial metabolism in Wnt-dependent pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C01.