ArticleInternational journal of molecular sciences2021
A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches.
Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed, 4 citations in OpenAlex.
- Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature.NPJ precision oncology · 2023Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
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Abstract
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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