A gene expression signature to predict nucleotide excision repair defects and novel therapeutic approaches

Rongbin Wei, Hui Dai, Jing Zhang, David J.H. Shih, Yulong Liang, Pengfeng Xiao, Daniel J. McGrail, Shiaw Yih Lin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5008
JournalInternational journal of molecular sciences
Volume22
Issue number9
DOIs
StatePublished - May 1 2021

Keywords

  • Breast cancer
  • Cancer treatment
  • Gene expression signature
  • Novel therapeutic approaches
  • Nucleotide excision repair defects

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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