Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer.
Xudong ZhangYao JunXiaoran LiNa NiuYan LiuRichard A HajekGuang PengShannon Neville WestinAnil K SoodJinsong LiuPublished in: Science advances (2023)
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.
Keyphrases
- high grade
- induced apoptosis
- combination therapy
- single cell
- cell cycle arrest
- high glucose
- dna damage
- drug induced
- cell therapy
- diabetic rats
- cancer therapy
- endoplasmic reticulum stress
- endothelial cells
- emergency department
- squamous cell carcinoma
- dna repair
- stem cells
- drug delivery
- signaling pathway
- cell proliferation
- papillary thyroid
- young adults
- squamous cell
- bone marrow
- childhood cancer