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PROTAC-mediated conditional degradation of the WRN helicase as a potential strategy for selective killing of cancer cells with microsatellite instability

Tejwani, Vikram ; Carroll, Thomas ; Macartney, Thomas ; Bandau, Susanne ; Alabert, Constance ; Saredi, Giulia LU ; Toth, Rachel and Rouse, John (2024) In Scientific Reports 14(1).
Abstract

Multiple studies have demonstrated that cancer cells with microsatellite instability (MSI) are intolerant to loss of the Werner syndrome helicase (WRN), whereas microsatellite-stable (MSS) cancer cells are not. Therefore, WRN represents a promising new synthetic lethal target for developing drugs to treat cancers with MSI. Given the uncertainty of how effective inhibitors of WRN activity will prove in clinical trials, and the likelihood of tumours developing resistance to WRN inhibitors, alternative strategies for impeding WRN function are needed. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that target specific proteins for degradation. Here, we engineered the WRN locus so that the gene product is... (More)

Multiple studies have demonstrated that cancer cells with microsatellite instability (MSI) are intolerant to loss of the Werner syndrome helicase (WRN), whereas microsatellite-stable (MSS) cancer cells are not. Therefore, WRN represents a promising new synthetic lethal target for developing drugs to treat cancers with MSI. Given the uncertainty of how effective inhibitors of WRN activity will prove in clinical trials, and the likelihood of tumours developing resistance to WRN inhibitors, alternative strategies for impeding WRN function are needed. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that target specific proteins for degradation. Here, we engineered the WRN locus so that the gene product is fused to a bromodomain (Bd)-tag, enabling conditional WRN degradation with the AGB-1 PROTAC specific for the Bd-tag. Our data revealed that WRN degradation is highly toxic in MSI but not MSS cell lines. In MSI cells, WRN degradation caused G
2/M arrest, chromosome breakage and ATM kinase activation. We also describe a multi-colour cell-based platform for facile testing of selective toxicity in MSI versus MSS cell lines. Together, our data show that a degrader approach is a potentially powerful way of targeting WRN in MSI cancers and paves the way for the development of WRN-specific PROTAC compounds.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Humans, Werner Syndrome Helicase/metabolism, Microsatellite Instability/drug effects, Proteolysis/drug effects, Cell Line, Tumor, Neoplasms/drug therapy, Ataxia Telangiectasia Mutated Proteins/metabolism
in
Scientific Reports
volume
14
issue
1
article number
20824
publisher
Nature Publishing Group
external identifiers
  • pmid:39242638
  • scopus:85203296420
ISSN
2045-2322
DOI
10.1038/s41598-024-71160-5
language
English
LU publication?
no
additional info
© 2024. The Author(s).
id
e743ff16-583e-487b-9ac8-73a3f4e945dd
date added to LUP
2025-11-03 10:59:15
date last changed
2025-11-18 05:07:12
@article{e743ff16-583e-487b-9ac8-73a3f4e945dd,
  abstract     = {{<p>Multiple studies have demonstrated that cancer cells with microsatellite instability (MSI) are intolerant to loss of the Werner syndrome helicase (WRN), whereas microsatellite-stable (MSS) cancer cells are not. Therefore, WRN represents a promising new synthetic lethal target for developing drugs to treat cancers with MSI. Given the uncertainty of how effective inhibitors of WRN activity will prove in clinical trials, and the likelihood of tumours developing resistance to WRN inhibitors, alternative strategies for impeding WRN function are needed. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that target specific proteins for degradation. Here, we engineered the WRN locus so that the gene product is fused to a bromodomain (Bd)-tag, enabling conditional WRN degradation with the AGB-1 PROTAC specific for the Bd-tag. Our data revealed that WRN degradation is highly toxic in MSI but not MSS cell lines. In MSI cells, WRN degradation caused G <br>
 2/M arrest, chromosome breakage and ATM kinase activation. We also describe a multi-colour cell-based platform for facile testing of selective toxicity in MSI versus MSS cell lines. Together, our data show that a degrader approach is a potentially powerful way of targeting WRN in MSI cancers and paves the way for the development of WRN-specific PROTAC compounds.<br>
 </p>}},
  author       = {{Tejwani, Vikram and Carroll, Thomas and Macartney, Thomas and Bandau, Susanne and Alabert, Constance and Saredi, Giulia and Toth, Rachel and Rouse, John}},
  issn         = {{2045-2322}},
  keywords     = {{Humans; Werner Syndrome Helicase/metabolism; Microsatellite Instability/drug effects; Proteolysis/drug effects; Cell Line, Tumor; Neoplasms/drug therapy; Ataxia Telangiectasia Mutated Proteins/metabolism}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{PROTAC-mediated conditional degradation of the WRN helicase as a potential strategy for selective killing of cancer cells with microsatellite instability}},
  url          = {{http://dx.doi.org/10.1038/s41598-024-71160-5}},
  doi          = {{10.1038/s41598-024-71160-5}},
  volume       = {{14}},
  year         = {{2024}},
}