Eprenetapopt in combination with carboplatin in high-grade ovarian and triple negative breast cancer cell lines with acquired resistance to olaparib

Abstract

High-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) frequently exhibit mutations in DNA damage response (DDR) genes, as BRCA1, BRCA2 and TP53, which are associated with chemotherapy sensitivity. Olaparib, a PARP inhibitor, provides the greatest clinical benefit as maintenance therapy in HGSOC—particularly in tumors with BRCA1/2 mutations or broader homologous recombination deficiency (HRD)—whereas benefit in HRD−negative disease is limited. Eprenetapopt (APR-246) restores wild-type p53 function in tumor cells with TP53 mutations. This study investigates the potential of combining eprenetapopt with carboplatin to overcome resistance to the PARP inhibitor (PARPi) olaparib in HGSOC and TNBC cell lines. Combining eprenetapopt with carboplatin shows promising preclinical efficacy by enhancing cytotoxicity in olaparib−resistant models and demonstrating synergistic interaction; these data support the combination as a potential strategy to mitigate PARPi resistance and carboplatin cross−resistance in TP53 mutant HGSOC and TNBC cell lines.