Abstract 2673: Several LSD1 inhibitors have a potential to disturb fatty acid metabolism necessary &It glycolysis-inhibited pancreatic cancers to survive

Abstract

Abstract Despite increased aerobic glycolysis is generally seen in human cancers, pancreatic ductal adenocarcinoma (PDAC) cells keep alive in glycolysis-suppressed conditions (1). Here, we sought there are potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anti-cancer metabolism compounds, we identified SP2509, a selective lysine specific demethylase 1 (LSD1) inhibitor (2). We also tested the effect of another three LSD1 inhibitors (Iadademstat, OG-L002 and T-3775440) on PDAC cells viability. The results showed that OG-L002, but not Iadademstat or T-3775440, lowered glycolysis-suppressed PDAC cells viability, like SP2509. Importantly, only knockdown of LSD1 or LSD2 failed to lower the viability of glycolysis suppressed PDAC cells. In our previous study, we proved that glucose-starvation make PDAC cells yield survival to mitochondrial oxidative phosphorylation (1). In this study, we cleared fatty acids metabolism played a crucial role for glycolysis suppressed PDAC cells survival. Then, we confirmed that SP2509 and OG-L002 can lead lipid droplets accumulation in glycolysis-suppressed conditions. In conclusion, our results showed that SP2509 and OG-L002 may involve regulatory effects on lipid droplets homeostasis, which control storage and release of fatty acids, not only by targeting LSD1 or LSD2. Moreover, SP2509 and OG-L002 significantly lowered viability of glycolysis-suppressed PDAC cells, supposing a novel therapeutic potential of approaches to override resistance of glucose-starvation in PDAC cells. 1.Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H, Chibana H, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019;9(1):18699. 2.Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SGT, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2017;31(7):1658. Citation Format: Zhiheng Zhang, Haruna Aoki, Keitaro Umezawa, Taichi Oshima, Takuya Hirao, Yuri Miura, Kousei Ito, Shigeki Aoki. Several LSD1 inhibitors have a potential to disturb fatty acid metabolism necessary &It glycolysis-inhibited pancreatic cancers to survive [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2673.