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Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR.

Authors
  • Zong, Dali1
  • Koussa, Natasha C2
  • Cornwell, James A3
  • Pankajam, Ajith V2
  • Kruhlak, Michael J3
  • Wong, Nancy2
  • Chari, Raj4
  • Cappell, Steven D3
  • Nussenzweig, André1
  • 1 Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; [email protected] [email protected].
  • 2 Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 3 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 4 Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
Type
Published Article
Journal
Genes & development
Publication Date
Oct 01, 2023
Volume
37
Issue
19-20
Pages
913–928
Identifiers
DOI: 10.1101/gad.351085.123
PMID: 37932011
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN-knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We found that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we found no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low-dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provide the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggest that dual targeting of WRN and ATR might be a useful strategy for treating MSI-H cancers. Published by Cold Spring Harbor Laboratory Press.

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