Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency

Lena J. McLaughlin, Lora Stojanovic, Aksinija A. Kogan, Julia L. Rutherford, Eun Yong Choi, Ray Whay Chiu Yen, Limin Xia, Ying Zou, Rena G. Lapidus, Stephen B. Baylin, Michael J. Topper, Feyruz V. Rassool

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)17785-17795
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
StatePublished - Jul 28 2020
Externally publishedYes


  • DNA methyltransferase inhibitors
  • Fanconi anemia
  • Homologous recombination deficiency
  • Poly(ADP-ribose) polymerase inhibitors
  • Stimulator of interferon signaling

ASJC Scopus subject areas

  • General


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