Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

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ID: 81481
2019
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Abstract
Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.
Reference Key
elliott2019lysosomeproceedings Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Elliott, Irmina A;Dann, Amanda M;Xu, Shili;Kim, Stephanie S;Abt, Evan R;Kim, Woosuk;Poddar, Soumya;Moore, Alexandra;Zhou, Lei;Williams, Jennifer L;Capri, Joseph R;Ghukasyan, Razmik;Matsumura, Cynthia;Tucker, D Andrew;Armstrong, Wesley R;Cabebe, Anthony E;Wu, Nanping;Li, Luyi;Le, Thuc M;Radu, Caius G;Donahue, Timothy R;
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2019
DOI
10.1073/pnas.1812410116
URL
Keywords
Pancreatic cancer autophagy lysosome replication stress nucleotide metabolism

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