title: Acetyl-CoA carboxylase inhibitors attenuate WNT and Hedgehog signaling and suppress pancreatic tumor growth.
abstract: Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects. Treatment with ACC inhibitors blocked tumor growth and converted the poorly differentiated histological phenotype to epithelial phenotype in multiple cell line-based and patient-derived pancreatic cancer xenograft models. Together, our data highlight the potential utility of ACC inhibitors for pancreatic cancer treatment, and provide novel insight into the link between upregulated de novo fatty acid synthesis in cancer cells, protein lipidation, and oncogenic signaling.
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.|Current address: Merck KGaA, Darmstadt, Germany.
authors.forename: Elissaveta
authors.initials: E
authors.lastname: Petrova
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Paul
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sturz
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Haike
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Siegel
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany.
authors.forename: Ningshu
authors.initials: N
authors.lastname: Liu
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism*; D060509:Wnt3A Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D051153:Wnt Proteins; D060509:Wnt3A Protein; D000103:Acetyl-CoA Carboxylase
keywords: ACC; Hedgehog; PDAC; WNT; lipidation