Distinct effects of sacituzumab govitecan and berzosertib on DNA damage response in ovarian cancer

Antibody-drug conjugates (ADCs) have become an important class of anticancer drugs in solid tumors including drug-resistant gynecologic malignancies. TROP2 is a cell surface antigen that is highly expressed in ovarian carcinoma (OC) but minimally expressed in normal ovarian tissues. In this study, we aimed to identify how TROP2-specific ADC, sacituzumab govitecan (SG), modulates DNA damage response pathways in drug-resistant OC. We found that SG induces G2/M arrest, increases RPA1 foci, and decreases replication fork speed, resulting in replication stress in TROP2-positive cells while these were less evident in TROP2-negative cells. In OC in vitro and in vivo models, SN-38 sensitivity and TROP2 expression play key roles in response to either ATR inhibitor or SG alone, or in combination. Additionally, inhibition of translesion DNA synthesis enhances SG and PARP inhibitor (PARPi) sensitivity in PARPi-resistant OC cells. These findings provide mechanistic insights for clinical development of SG in drug-resistant OC. Overall design: RNA sequencing (RNAseq) data were obtained from total RNA from fresh frozen tumor biopsy samples from 15 BRCAmut HGSOC patients and 20 BRCAwt HGSOC patients enrolled in the clinical trial at the National Cancer Institute (ClinicalTrials.gov, NCT02203513). RNAseq was performed using a HiSeq4000 sequencing system (Illumina) at the CCR Sequencing Facility/NCI. Paired-end sequencing was done. Quartile normalization and log-transformation prior to analysis were performed on datasets.