Targeting Polyploid Giant Cancer Cells Potentiates a Therapeutic Response and Overcomes Resistance to Parp Inhibitors in Ovarian Cancer

Authors

Xudong Zhang
Jun Yao
Xiaoran Li
Na Niu
Yan Liu
Richard A Hajek
Guang Peng
Shannon Westin
Anil K Sood
Jinsong Liu

Publication Date

7-21-2023

Journal

Science Advances

Abstract

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.

Keywords

Polyploidy, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Humans, Female, Mifepristone, Drug Resistance, Neoplasm, Cellular Senescence, Cell Line, Tumor, Apoptosis

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Supplementary Materials

PMID: 37478190