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.
journal_name
Proc Natl Acad Sci U S Aauthors
McLaughlin LJ,Stojanovic L,Kogan AA,Rutherford JL,Choi EY,Yen RC,Xia L,Zou Y,Lapidus RG,Baylin SB,Topper MJ,Rassool FVdoi
10.1073/pnas.2003499117subject
Has Abstractpub_date
2020-07-28 00:00:00pages
17785-17795issue
30eissn
0027-8424issn
1091-6490pii
2003499117journal_volume
117pub_type
杂志文章abstract::Bacteriophage Mu was inserted into the unc genes of Escherichia coli. The resulting mutation AS12 had a polar effect on the unc operon: membranes of the mutant AS12 contained the dicyclohexylcarbodiimide-binding protein c and the protein a as sole subunits of the ATP synthase. It was shown by peptide mapping and amino...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.78.11.6643
更新日期:1981-11-01 00:00:00
abstract::An electrophoretic karyotype of Aspergillus nidulans has been obtained using contour-clamped homogeneous electric field gel electrophoresis. Six chromosomal bands were separated, with two of the bands migrating as doublets. Using the Schizosaccharomyces pombe and Saccharomyces cerevisiae chromosomes as size standards,...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.16.6260
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.22.7738
更新日期:1985-11-01 00:00:00
abstract::The polymerization of individual RecA-DNA filaments, containing either single-stranded or double-stranded DNA, was followed in real time, and their mechanical properties were characterized with force-measuring laser tweezers. It was found that the stretch modulus of a filament is dominated by its (central) DNA compone...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.96.18.10109
更新日期:1999-08-31 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.12.4212
更新日期:1985-06-01 00:00:00
abstract::The caspases are cysteine proteases that have been implicated in the execution of programmed cell death in organisms ranging from nematodes to humans. Many members of the Bcl-2 family, including Bcl-XL, are potent inhibitors of programmed cell death and inhibit activation of caspases in cells. Here, we report a direct...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.95.2.554
更新日期:1998-01-20 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0510157103
更新日期:2006-04-25 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1611431114
更新日期:2017-01-03 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.11.3533
更新日期:1985-06-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.78.4.2150
更新日期:1981-04-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.74.9.3657
更新日期:1977-09-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2004-04-06 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0706032105
更新日期:2008-05-20 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0409042102
更新日期:2005-01-25 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.18.6711
更新日期:1986-09-01 00:00:00
abstract::We obtain a classification of the irreducible (nonunitary) representations of a connected semisimple Lie group G, in terms of their restriction to a maximal compact subgroup K of G. (A classification in terms of analytic properties of the representations has been given by R. P. Langlands [(1973), mimeographed notes, I...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.74.7.2649
更新日期:1977-07-01 00:00:00