AUTHOR=Baquero Juan Miguel , Marchena-Perea Erik , Mirabet Rocío , Torres-Ruiz Raúl , Blanco-Aparicio Carmen , Rodríguez-Perales Sandra , Helleday Thomas , Benítez-Buelga Carlos , Benítez Javier , Osorio Ana 

TITLE=OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.888810

DOI=10.3389/fonc.2022.888810

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>PARP1 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 <italic>BRCA1/2</italic> 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.</p></sec><sec><title>Methods</title><p>We 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.</p></sec><sec><title>Results</title><p>Knocking out <italic>BRCA1</italic> 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 <italic>BRCA1</italic> deficiency, reflecting an additive interaction.</p></sec><sec><title>Discussion</title><p>These results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in <italic>BRCA1</italic>-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.</p></sec>