Abstract C078: Inhibiting the autophagy-lysosomal pathway in pancreatic ductal adenocarcinoma using novel small molecules

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of 11.5% due to poor early detection and a lack of effective therapies. To meet the energetic demands, PDAC relies on autophagy to sustain growth and proliferation. Autophagy inhibitors such as hydroxychloroquine (HCQ) only showed limited autophagy inhibition in vivo and failed to provide clinical benefit to patients. However, studies have shown that the combination of HCQ and the MEK/ERK inhibitors can render better therapeutic results with stronger cytotoxicity. Our lab has designed and developed a class of small molecules (GN compounds) that target the autophagy-lysosomal pathway (ALP). Our GN compounds show autophagy inhibition and induction of extrinsic apoptosis markers by Western blot. Furthermore, GN64 affects the function of endosomes and lysosomes by immunofluorescence (IF). The combination treatment of GN79 and Binimetinib, a MEKi, inhibits the ALP and confers enhanced cytotoxicity in a panel of human PDAC cell lines. Future directions are aimed at determining the protein target and mechanism of GN compounds that leads to ALP inhibition. Completion of this project will advance the therapeutic development of novel ALP inhibitors and advance our understanding of the ALP with the possibility to imrpove the current therapeutic regimen for PDAC patients. Citation Format: Yangjingyi Ruan, Daniel W. Worroll, Grady Nelson, Yue-Ming Li. Inhibiting the autophagy-lysosomal pathway in pancreatic ductal adenocarcinoma using novel small molecules [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C078.