Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 30; pp. 17785 - 17795
• Main Authors: McLaughlin, Lena J., Stojanovic, Lora, Kogan, Aksinija A., Rutherford, Julia L., Choi, Eun Yong, Yen, Ray-Whay Chiu, Xia, Limin, Zou, Ying, Lapidus, Rena G., Baylin, Stephen B., Topper, Michael J., Rassool, Feyruz V.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.07.2020
• Subjects: Adenosine diphosphate; Biological Sciences; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Breast cancer; Cancer; Cell Line, Tumor; Computational Biology; Deoxyribonucleic acid; DNA; DNA damage; DNA methyltransferase; DNA Modification Methylases - antagonists & inhibitors; DNA repair; DNA Repair - drug effects; Epigenetics; Fanconi Anemia - genetics; Female; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genomes; Homologous recombination; Homologous Recombination - drug effects; Homology; Humans; Immunity, Innate - drug effects; Inflammasomes; Inhibitors; Interferon; Interferons - metabolism; Membrane Proteins - metabolism; Models, Biological; Mutation; Ovarian cancer; Phenotypes; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Repair; Ribose; Sensitizing; Signal Transduction - drug effects; Signaling; Stimulators; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Necrosis Factor-alpha - metabolism; DNA methyltransferase inhibitors; Fanconi anemia; poly(ADP-ribose) polymerase inhibitors; stimulator of interferon signaling; homologous recombination deficiency
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2003499117

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 awidespread 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.