A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches
Open accessAbstract
Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.
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Prior work has assessed the utility of mutational and transcriptomic signatures in predicting response to cisplatin, but none of these advancements have been translated into routine clinical care.
“Given its widespread use, it comes as no surprise that prior work has assessed the utility of mutational and transcriptomic signatures in predicting response to this drug; yet, to the best knowledge of these authors, none of these advancements have been translated into routine clinical care15–19.”
From Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature (2023) · cites this paper as [18]
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Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature
Scarborough, J. A., Eschrich, S. A., Torres-Roca, J., Dhawan, A., & Scott, J. G. (2023) · npj Precision Oncology · doi:10.1038/s41698-023-00375-y · Cited by 14 · see citing works
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Exploiting convergent evolution to derive a pan-cancer cisplatin response gene expression signaturePreprint
Scarborough, J. A., Eschrich, S. A., Torres–Roca, J. F., Dhawan, A., & Scott, J. G. (2021) · medRxiv · doi:10.1101/2021.11.10.21265799 · Cited by 1 · see citing works
Maćkowiak, B., Ostrowska, K., Kozikowska, J., Kulcenty, K., Golusiński, W., & Suchorska, W. (2026) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-026-06563-0
- Authors
- Wei, R., Dai, H., Zhang, J., Shih, D. J. H., Liang, Y., Xiao, P., McGrail, D. J., & Lin, S.-Y.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- McGrail, Daniel J.
- Lin, Shiaw-Yih
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-05-08
- Volume
- 22
- Issue
- 9
- Pages
- 5008
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8125907
- OpenAlex
- W3161930347
- Cited by
- 4
- References
- 45
- Citations by year
- 2026: 1 · 2023: 2 · 2021: 1
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- nucleotide excision repair, DNA repair deficiency, gene expression signatures, synthetic lethality, GSK3 inhibition, cisplatin, drug repurposing, isogenic cell lines, UV-induced DNA damage, DNA adducts, cancer susceptibility, premature aging, treatment stratification
- MeSH terms
- DNA Repair, Humans, Neoplasms, Reproducibility of Results, Gene Expression Regulation, Neoplastic, Gene Expression Profiling, Cell Line, Tumor
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