@article{b17f90cb7de04fc090d6d5025f0c8f79,
title = "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.",
keywords = "DNA methyltransferase inhibitors, Fanconi anemia, Homologous recombination deficiency, Poly(ADP-ribose) polymerase inhibitors, Stimulator of interferon signaling",
author = "McLaughlin, {Lena J.} and Lora Stojanovic and Kogan, {Aksinija A.} and Rutherford, {Julia L.} and Choi, {Eun Yong} and Yen, {Ray Whay Chiu} and Limin Xia and Ying Zou and Lapidus, {Rena G.} and Baylin, {Stephen B.} and Topper, {Michael J.} and Rassool, {Feyruz V.}",
note = "Funding Information: Our studies have been supported by funding from the Van Andel Institute–Stand up to Cancer (S.B.B. and F.V.R.); the Adelson Medical Research Foundation (L.J.M., L.S., J.L.R., M.J.T., F.V.R., and S.B.B.); Evelyn Grollman Glick Scholar (M.J.T.); The Hodson Trust (M.J.T.); the Leukemia Lymphoma Society (A.A.K. and F.V.R.); the Maryland Department of Health{\textquoteright}s Cigarette Restitution Fund Program (F.V.R.); the National Cancer Institute–Cancer Center Support Grant P30 CA134274 University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (R.G.L., E.Y.C., and F.V.R.); the Molecular Medicine Graduate Program, University of Maryland (L.J.M., and A.A.K.); the Biochemistry Graduate Program, University of Maryland (J.L.R.); and the Human Genetics Graduate Program, University of Maryland (L.S.). R.-W.C.Y. is supported by the Commonwealth Foundation and the Defense Health Program, through the Department of Defense Ovarian Cancer Research Program, Teal Innovator Award OC130454/W81XWH-14-1-0385. Opinions, interpretations, conclusions, and recommendations are those of the authors and not necessarily endorsed by the Department of Defense. Funding Information: ACKNOWLEDGMENTS. Our studies have been supported by funding from the Van Andel Institute–Stand up to Cancer (S.B.B. and F.V.R.); the Adelson Medical Research Foundation (L.J.M., L.S., J.L.R., M.J.T., F.V.R., and S.B.B.); Evelyn Grollman Glick Scholar (M.J.T.); The Hodson Trust (M.J.T.); the Leukemia Lymphoma Society (A.A.K. and F.V.R.); the Maryland Department of Health{\textquoteright}s Cigarette Restitution Fund Program (F.V.R.); the National Cancer Institute–Cancer Center Support Grant P30 CA134274 University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (R.G.L., E.Y.C., and F.V.R.); the Molecular Medicine Graduate Program, University of Maryland (L.J.M., and A.A.K.); the Biochemistry Graduate Program, University of Maryland (J.L.R.); and the Human Genetics Graduate Program, University of Maryland (L.S.). R.-W.C.Y. is supported by the Commonwealth Foundation and the Defense Health Program, through the Department of Defense Ovarian Cancer Research Program, Teal Innovator Award OC130454/ W81XWH-14-1-0385. Opinions, interpretations, conclusions, and recommendations are those of the authors and not necessarily endorsed by the Department of Defense. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jul,
day = "28",
doi = "10.1073/pnas.2003499117",
language = "English (US)",
volume = "117",
pages = "17785--17795",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "30",
}