OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells
BackgroundPARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, t...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.888810/full |
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| author | Juan Miguel Baquero Erik Marchena-Perea Rocío Mirabet Raúl Torres-Ruiz Raúl Torres-Ruiz Carmen Blanco-Aparicio Sandra Rodríguez-Perales Thomas Helleday Thomas Helleday Carlos Benítez-Buelga Javier Benítez Javier Benítez Ana Osorio Ana Osorio Ana Osorio |
| author_facet | Juan Miguel Baquero Erik Marchena-Perea Rocío Mirabet Raúl Torres-Ruiz Raúl Torres-Ruiz Carmen Blanco-Aparicio Sandra Rodríguez-Perales Thomas Helleday Thomas Helleday Carlos Benítez-Buelga Javier Benítez Javier Benítez Ana Osorio Ana Osorio Ana Osorio |
| author_sort | Juan Miguel Baquero |
| collection | DOAJ |
| description | BackgroundPARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.MethodsWe hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.ResultsKnocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction.DiscussionThese results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer. |
| first_indexed | 2024-12-12T02:58:11Z |
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| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T02:58:11Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-bd4acf3e7436440d9c1a0f93ca759fae2022-12-22T00:40:41ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-05-011210.3389/fonc.2022.888810888810OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC CellsJuan Miguel Baquero0Erik Marchena-Perea1Rocío Mirabet2Raúl Torres-Ruiz3Raúl Torres-Ruiz4Carmen Blanco-Aparicio5Sandra Rodríguez-Perales6Thomas Helleday7Thomas Helleday8Carlos Benítez-Buelga9Javier Benítez10Javier Benítez11Ana Osorio12Ana Osorio13Ana Osorio14Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainFamilial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainHuman Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainMolecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainDivision of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, SpainExperimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, SpainMolecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenSheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United KingdomScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenHuman Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainSpanish Network on Rare Diseases (CIBERER), Madrid, SpainHuman Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainFamilial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, SpainSpanish Network on Rare Diseases (CIBERER), Madrid, SpainBackgroundPARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.MethodsWe hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.ResultsKnocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction.DiscussionThese results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.https://www.frontiersin.org/articles/10.3389/fonc.2022.888810/fullBRCA1OGG1 inhibitorPARP1 inhibitortriple negative breast cancersynthetic lethality |
| spellingShingle | Juan Miguel Baquero Erik Marchena-Perea Rocío Mirabet Raúl Torres-Ruiz Raúl Torres-Ruiz Carmen Blanco-Aparicio Sandra Rodríguez-Perales Thomas Helleday Thomas Helleday Carlos Benítez-Buelga Javier Benítez Javier Benítez Ana Osorio Ana Osorio Ana Osorio OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells Frontiers in Oncology BRCA1 OGG1 inhibitor PARP1 inhibitor triple negative breast cancer synthetic lethality |
| title | OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells |
| title_full | OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells |
| title_fullStr | OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells |
| title_full_unstemmed | OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells |
| title_short | OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells |
| title_sort | ogg1 inhibition triggers synthetic lethality and enhances the effect of parp inhibitor olaparib in brca1 deficient tnbc cells |
| topic | BRCA1 OGG1 inhibitor PARP1 inhibitor triple negative breast cancer synthetic lethality |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.888810/full |
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