Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency.

Abstract:

: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.

authors

McLaughlin LJ,Stojanovic L,Kogan AA,Rutherford JL,Choi EY,Yen RC,Xia L,Zou Y,Lapidus RG,Baylin SB,Topper MJ,Rassool FV

doi

10.1073/pnas.2003499117

subject

Has Abstract

pub_date

2020-07-28 00:00:00

pages

17785-17795

issue

30

eissn

0027-8424

issn

1091-6490

pii

2003499117

journal_volume

117

pub_type

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