Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion

Irmina A. Elliott(University of California, Los Angeles), Amanda M. Dann(University of California, Los Angeles), Shili Xu(University of California, Los Angeles), Stephanie Kim(University of California, Los Angeles), Evan R. Abt(University of California, Los Angeles), Woosuk Kim(University of California, Los Angeles), Soumya Poddar(University of California, Los Angeles), Alexandra M. Moore(University of California, Los Angeles), Lei Zhou(University of California, Los Angeles), Jennifer L. Williams(UCLA Medical Center), Joseph Capri(University of California, Los Angeles), Razmik Ghukasyan(University of California, Los Angeles), Cynthia Matsumura(University of California, Los Angeles), D. Andrew Tucker(University of California, Los Angeles), Wesley R. Armstrong(University of California, Los Angeles), Anthony E. Cabebe(University of California, Los Angeles), Nanping Wu(University of California, Los Angeles), Luyi Li(University of California, Los Angeles), Thuc Le(University of California, Los Angeles), Caius G. Radu(University of California, Los Angeles), Timothy R. Donahue(University of California, Los Angeles)
Proceedings of the National Academy of Sciences
March 20, 2019
10.1073/pnas.1812410116
Cited by 51Open Access
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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.

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