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  • 标题:Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency
  • 本地全文:下载
  • 作者:Lena J. McLaughlin ; Lora Stojanovic ; Aksinija A. Kogan
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2020
  • 卷号:117
  • 期号:30
  • 页码:17785-17795
  • DOI:10.1073/pnas.2003499117
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in triple negative breast (TNBC) and ovarian cancers (OCs) harboring BRCA mutations, generating homologous recombination deficiencies (HRDs). DNA methyltransferase inhibitors (DNMTi) increase PARP trapping and reprogram the DNA damage response to generate HRD, sensitizing BRCA-proficient cancers to PARPi. We now define the mechanisms through which HRD is induced in BRCA-proficient TNBC and OC. DNMTi in combination with PARPi up-regulate broad innate immune and inflammasome-like signaling events, driven in part by stimulator of interferon genes (STING), to unexpectedly directly generate HRD. This inverse relationship between inflammation and DNA repair is critical, not only for the induced phenotype, but also appears as a widespread occurrence in The Cancer Genome Atlas datasets and cancer subtypes. These discerned interactions between inflammation signaling and DNA repair mechanisms now elucidate how epigenetic therapy enhances PARPi efficacy in the setting of BRCA-proficient cancer. This paradigm will be tested in a phase I/II TNBC clinical trial.
  • 关键词:homologous recombination deficiency ; Fanconi anemia ; stimulator of interferon signaling ; poly(ADP-ribose) polymerase inhibitors ; DNA methyltransferase inhibitors
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