Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion

• DOI: 10.1073/pnas.1812410116
• Publication Date: 2019-03-20T23:15:39Z
• Authors: Irmina A. Elliott; Amanda M. Dann; Shili Xu; Stephanie S. Kim; Evan R. Abt; Woosuk Kim; Soumya Poddar; Alexandra Moore; Lei Zhou; Jennifer L. Williams; Joseph R. Capri; Razmik Ghukasyan; Cynthia Matsumura; D. Andrew Tucker; Wesley R. Armstrong; Anthony E. Cabebe; Nanping Wu; Luyi Li; Thuc M. Le; Caius G. Radu; Timothy R. Donahue
• Keywords: Male; 0301 basic medicine; autophagy; replication stress; Physiological; pancreatic cancer; 610; nucleotide metabolism; Stress; Cell Line; Pancreatic Cancer; Mice; 03 medical and health sciences; Rare Diseases; Stress, Physiological; Cell Line, Tumor; 2.1 Biological and endogenous factors; Animals; Humans; Cancer; Aspartic Acid; Tumor; Carcinoma; Chloroquine; Biological Sciences; Xenograft Model Antitumor Assays; Mitochondria; 3. Good health; Pancreatic Neoplasms; Orphan Drug; 5.1 Pharmaceuticals; Pancreatic Ductal; lysosome; Female; Biochemistry and Cell Biology; Digestive Diseases; Lysosomes; Carcinoma, Pancreatic Ductal

SignificancePancreatic cancer is notoriously treatment resistant. These tumors rely on lysosome-dependent recycling pathways to generate substrates for metabolism, which are inhibited by chloroquine (CQ) and its derivatives. However, clinical efficacy of CQ as a monotherapy or combined with standard-of-care regimens has been limited. Using an unbiased kinome screen, we identify replication stress as an induced vulnerability of CQ due to impaired de novo nucleotide biosynthesis and find that combination treatment with CQ and a replication stress response inhibitor is synthetically lethal in pancreatic cancer.