Evidence map›Paper›PMID 30894490›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2019

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

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 and 11 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.

0numbers the graph read from it
0cells of the map it votes in
38citing papers in PubMed
2.8field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

38 citing papers in PubMed, 51 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Article
  5. Article
  6. Targeting Lysosomes for Enhanced Anti-Cancer Therapeutics and Immune Response.International journal of biological sciences · 2026
    Review
  7. mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Article
  8. Article
  9. Article
  10. Review
  11. Article
  12. Article
  13. Article
  14. Application ofMolecules (Basel, Switzerland) · 2022
    Article
  15. Review
  16. Article
  17. Review
  18. Article
  19. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 2 institutions in 2 countries.

Irmina A ElliottDepartment of Surgery, University of California, Los Angeles, CA 90095.
Amanda M DannDepartment of Surgery, University of California, Los Angeles, CA 90095.
Shili XuDepartment of Surgery, University of California, Los Angeles, CA 90095.ORCID 0000-0002-4933-8673
Stephanie S KimDepartment of Surgery, University of California, Los Angeles, CA 90095.
Evan R AbtDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Woosuk KimDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Soumya PoddarDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Alexandra MooreDepartment of Surgery, University of California, Los Angeles, CA 90095.
Lei ZhouDepartment of Surgery, University of California, Los Angeles, CA 90095.
Jennifer L WilliamsDepartment of Surgery, Harbor-UCLA Medical Center, Torrance, CA 90502.
Joseph R CapriDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Razmik GhukasyanDepartment of Surgery, University of California, Los Angeles, CA 90095.
Cynthia MatsumuraDepartment of Surgery, University of California, Los Angeles, CA 90095.
D Andrew TuckerDepartment of Surgery, University of California, Los Angeles, CA 90095.
Wesley R ArmstrongDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Anthony E CabebeDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Nanping WuDepartment of Surgery, University of California, Los Angeles, CA 90095.
Luyi LiDepartment of Surgery, University of California, Los Angeles, CA 90095.
Thuc M LeDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Caius G RaduDepartment of Surgery, University of California, Los Angeles, CA 90095; cradu@mednet.ucla.edu TDonahue@mednet.ucla.edu.ORCID 0000-0002-9338-5397
Timothy R DonahueDepartment of Surgery, University of California, Los Angeles, CA 90095; cradu@mednet.ucla.edu TDonahue@mednet.ucla.edu.
University of California, Los Angeles · USUCLA Medical Center · US

Funding

UCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Yvonne Yu-Hsuan Chen · 2017 to 2026
$25.2M
GASTROENTEROLOGYT32DK007180 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JENSEN, DENNIS MICHAEL · 1986 to 2025
$10.0M
PET Imaging-guided Personalized Therapy in Pancreatic CancerR01CA187678 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CZERNIN, JOHANNES, DONAHUE, TIMOTHY R · 2014 to 2018
$2.8M
NCI NIH HHS P50 CA211015NCI NIH HHS R01 CA187678NIDDK NIH HHS T32 DK007180
6 · The paper itself

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.

Indexed as

Carcinoma, Pancreatic DuctalMitochondriaPancreatic NeoplasmsAnimalsAspartic AcidCell Line, TumorChloroquineFemaleHumansLysosomesMaleMiceStress, PhysiologicalXenograft Model Antitumor AssaysAspartic AcidChloroquineautophagylysosomenucleotide metabolismpancreatic cancerreplication stress

Identifiers

PMID30894490
PMCPMC6452719
OpenAlexW2922764110

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.