Introduction Ovarian cancer is the most lethal gynaecological cancer worldwide. Poly-ADP-ribose (PARP) inhibitors have greatly improved the prognosis, especially for patients with BRCA-mutant ovarian cancer. However, resistance is a clinically important problem. Sacituzumab govitecan (SG) is an antibody-drug conjugate targeting TROP2. SG contains a topoisomerase I inhibitor as a cytotoxic agent and is approved for the treatment of certain breast cancers. TROP2 is commonly overexpressed in ovarian cancer and overexpression correlates with poorer survival. This study aimed to determine the mechanisms of resistance to olaparib and explore the potential of SG to overcome resistance.

Methods Olaparib-resistant PEO1 (PEO1-Ola) cells were generated through continuous exposure of PEO1 cells to olaparib, to a maximum 13 μM, for four months. Apoptosis induction by single agent SG, talazoparib and olaparib and combinations was investigated using kinetic, fluorescent microscopy with the Incucyte S3 imaging system. RNA sequencing was used to identify differential gene expression between PEO1-Ola and PEO1 cells.

Results The combination of SG with either PARP inhibitors overcame olaparib resistance and synergistically resulted in induction of apoptosis in both cell lines. RNA sequencing showed increased activation of DNA damage response pathways as well as MYC and E2F targets in PEO1-Ola cells. Additionally, expression of members of the claudin protein family was increased; Claudin–1 overexpression was confirmed by Western Blotting.

Conclusion/Implications This pre-clinical study showed that SG in combination with PARPi can be used to overcome PARPi resistance in ovarian cancer and identified potential driver genes involved in olaparib resistance.