期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 30, 页码 17785-17795出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2003499117
关键词
homologous recombination deficiency; Fanconi anemia; stimulator of interferon signaling; poly(ADP-ribose) polymerase inhibitors; DNA methyltransferase inhibitors
资金
- Van Andel Institute-Stand up to Cancer
- Adelson Medical Research Foundation
- Evelyn Grollman Glick Scholar
- Hodson Trust
- Leukemia Lymphoma Society
- Maryland Department of Health's Cigarette Restitution Fund Program
- National Cancer Institute-Cancer Center Support Grant University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center [P30 CA134274]
- Molecular Medicine Graduate Program, University of Maryland
- Biochemistry Graduate Program, University of Maryland
- Human Genetics Graduate Program, University of Maryland
- Commonwealth Foundation
- Defense Health Program, through the Department of Defense Ovarian Cancer Research Program, Teal Innovator Award [OC130454/W81XWH-14-1-0385]
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 di-rectly 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.
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