Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6842-6847. doi: 10.1073/pnas.1812410116. Epub 2019 Mar 20.

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

Author information

1
Department of Surgery, University of California, Los Angeles, CA 90095.
2
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
3
Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095.
4
Department of Pancreatic and Thyroidal Surgery, Shengjing Hospital, China Medical University, Shenyang 110003, China.
5
Department of Surgery, Harbor-UCLA Medical Center, Torrance, CA 90502.
6
David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
7
Department of Surgery, University of California, Los Angeles, CA 90095; cradu@mednet.ucla.edu TDonahue@mednet.ucla.edu.
8
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.

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.

KEYWORDS:

autophagy; lysosome; nucleotide metabolism; pancreatic cancer; replication stress

PMID:
30894490
PMCID:
PMC6452719
[Available on 2019-09-20]
DOI:
10.1073/pnas.1812410116
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center