Journal
FRONTIERS IN ONCOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.888810
Keywords
BRCA1; OGG1 inhibitor; PARP1 inhibitor; triple negative breast cancer; synthetic lethality
Categories
Funding
- Spanish Ministry of Education, Culture and Sport [FPU15/01978]
- AECC scientific foundation
- Spanish National Research and Development Plan
- Instituto de Salud Carlos III [PI19/00640]
- FEDER [PI19/00640, PI17/02303, PI20/01837]
- AEI/MICIU EXPLORA Project [DTS19/00111]
- AECC_Lab_2020 Project (Asociacion Espanola Contra el Cancer)
- FEDER funds, H2020 BRIDGES project [FPU15/01978]
- Spanish Network on Rare Diseases (CIBERER)
- European Regional Development Fund (ERDF), A way to make Europe
- [BIO2017-91272-EXP]
- [FIS PI16/00440]
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This study found that OGG1 inhibition could serve as a synthetic lethality strategy and enhance the sensitivity to PARP inhibitors in BRCA1-deficient cells. This discovery provides a potential new framework for the treatment of hereditary breast and ovarian cancer.
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.
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