Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer
Menée à l'aide de lignées cellulaires, d'organoïdes dérivés de cancers séreux de haut grade de l'ovaire et de xénogreffes sur des modèles murins, cette étude met en évidence l'intérêt de cibler les cellules cancéreuses géantes polyploïdes pour lever la résistante aux inhibiteurs de PARP et améliorer l'efficacité de ces derniers
To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)–derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance. PARPi activates a pregnant-like process via forming polyploid giant cancer cells and is blocked by contraceptive drug RU-486.
Science Advances 2023