Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer.
Xudong Zhang, Jun Yao, Xiaoran Li, Na Niu, Yan Liu, Richard A Hajek, Guang Peng, Shannon Westin, Anil K Sood, Jinsong Liu
Author Information
Xudong Zhang: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Jun Yao: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Xiaoran Li: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Na Niu: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yan Liu: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Richard A Hajek: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Guang Peng: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Shannon Westin: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Anil K Sood: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
Jinsong Liu: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ORCID
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.
