Abstract 2242: Inhibition of acetyl-CoA carboxylase attenuates lipidation and activity of oncogenic signaling pathways in pancreatic cancer

Abstract

Abstract Normal cells can use circulating lipids, while some tumor cells require de novo biogenesis of fatty acids for survival irrespective of existing exogenous lipids. Acetyl-CoA Carboxylase (ACC) is the rate-limiting enzyme in the process of de novo fatty acid synthesis and one of its isoforms (ACC1) is overexpressed in various cancer types. We have developed a class of novel, potent small molecule inhibitors of ACC, which preferentially inhibit human ACC1 activity. Interestingly, in vitro the compounds are active in a selective subset of cancer cells, regardless of their proliferation rate, and pancreatic cancer cells are among the most sensitive cell lines to ACC1 inhibition both in vitro and in vivo. Notably, pancreatic cancer is characterized by alterations in several oncogenic pathways: KRAS, Hedgehog (Hh) and Wnt. One mechanism that modulates the activity of the above-mentioned oncogenic signaling molecules is protein lipidation. We hypothesized that in pancreatic cancer cells de novo fatty acid synthesis is an important source of lipids necessary for fully acting KRAS, Hh and Wnt molecules, and therefore the process is essential for cell proliferation and survival. To investigate this as potential novel anti-tumor mechanism of action, we conducted a series of experiments to assess the effect of ACC inhibition on these oncogenic pathways in vitro and in vivo. In vitro we first investigated the effect of ACC inhibition on Wnt secretion and activity, a process requiring lipidation of Wnt. Treatment of a Wnt3A-overexpressing cell line, L-Wnt3A, with the ACC inhibitor, indeed, leads to reduced Wnt3A protein levels secreted in the media. This result was further confirmed by the Super8xTOPFlash reporter assay in HEK293 cells incubated with conditional media from L-Wnt3A cells, with or without treatment with the ACC inhibitor. Furthermore, we showed that in Capan-2 cells, in which ligand-dependent autocrine Wnt signaling is active, treatment with the ACC inhibitor decreased the expression of β-catenin target genes and cell proliferation. In vivo profiling of the ACC inhibitor in a set of patient derived xenograft (PDX) models of pancreatic cancer indicated a correlation between the sensitivity to ACC inhibition and aberrant activation of Hh and Wnt signaling in the tumors, as shown by immunohistochemical detection of downstream targets of the two pathways. Currently, we are investigating the specific changes in Hh and Wnt signaling, following ACC inhibition in both a PDX model of pancreatic cancer, as well as in a Capan-2 xenograft mouse model. Together, these studies are building strong support for the hypothesis that tumor sensitivity to de novo fatty acid synthesis inhibition is linked to the dependence on multiple oncogenic signaling pathways that are regulated by protein lipidation, and highlight a potential new general approach for targeting ACC for the treatment of cancers. Citation Format: Elissaveta Petrova, Arne Scholz, Andrea Sturz, Juliane Paul, Franziska Siegel, Dominik Mumberg, Ningshu Liu. Inhibition of acetyl-CoA carboxylase attenuates lipidation and activity of oncogenic signaling pathways in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2242. doi:10.1158/1538-7445.AM2015-2242