Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effec...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2018
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| _version_ | 1826261667275603968 |
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| author | Gogola, E Duarte, AA de Ruiter, JR Wiegant, WW Schmid, JA de Bruijn, R James, DI Llobet, SG Vis, DJ Annunziato, S van den Broek, B Barazas, M Kersbergen, A van de Ven, M Tarsounas, M Ogilvie, DJ van Vugt, M Wessels, LFA Bartkova, J Gromova, I Andújar-Sánchez, M Bartek, J Lopes, M van Attikum, H Borst, P Jonkers, J Rottenberg, S |
| author_facet | Gogola, E Duarte, AA de Ruiter, JR Wiegant, WW Schmid, JA de Bruijn, R James, DI Llobet, SG Vis, DJ Annunziato, S van den Broek, B Barazas, M Kersbergen, A van de Ven, M Tarsounas, M Ogilvie, DJ van Vugt, M Wessels, LFA Bartkova, J Gromova, I Andújar-Sánchez, M Bartek, J Lopes, M van Attikum, H Borst, P Jonkers, J Rottenberg, S |
| author_sort | Gogola, E |
| collection | OXFORD |
| description | Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically. |
| first_indexed | 2024-03-06T19:24:57Z |
| format | Journal article |
| id | oxford-uuid:1b62fb10-05cf-456c-b76e-37937e5a51e6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:24:57Z |
| publishDate | 2018 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:1b62fb10-05cf-456c-b76e-37937e5a51e62022-03-26T11:00:10ZSelective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethalityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1b62fb10-05cf-456c-b76e-37937e5a51e6EnglishSymplectic ElementsCell Press 2018Gogola, EDuarte, AAde Ruiter, JRWiegant, WWSchmid, JAde Bruijn, RJames, DILlobet, SGVis, DJAnnunziato, Svan den Broek, BBarazas, MKersbergen, Avan de Ven, MTarsounas, MOgilvie, DJvan Vugt, MWessels, LFABartkova, JGromova, IAndújar-Sánchez, MBartek, JLopes, Mvan Attikum, HBorst, PJonkers, JRottenberg, SInhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically. |
| spellingShingle | Gogola, E Duarte, AA de Ruiter, JR Wiegant, WW Schmid, JA de Bruijn, R James, DI Llobet, SG Vis, DJ Annunziato, S van den Broek, B Barazas, M Kersbergen, A van de Ven, M Tarsounas, M Ogilvie, DJ van Vugt, M Wessels, LFA Bartkova, J Gromova, I Andújar-Sánchez, M Bartek, J Lopes, M van Attikum, H Borst, P Jonkers, J Rottenberg, S Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality |
| title | Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality |
| title_full | Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality |
| title_fullStr | Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality |
| title_full_unstemmed | Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality |
| title_short | Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality |
| title_sort | selective loss of parg restores parylation and counteracts parp inhibitor mediated synthetic lethality |
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