Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

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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.

Abstract

PARPi activates a pregnant-like process via forming polyploid giant cancer cells and is blocked by contraceptive drug RU-486.

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Most cited references 69

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Integrated Genomic Analyses of Ovarian Carcinoma

Nikolaus Schultz (2012)

Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.

Helen E. Bryant, Niklas Schultz, Huw Thomas … (2005)

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.

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PARP inhibitors: Synthetic lethality in the clinic.

Christopher J. Lord, Alan Ashworth (2017)

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.

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Author and article information

Contributors

Xudong Zhang:

ORCID: https://orcid.org/0000-0003-1896-4898

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Jun Yao:

ORCID: https://orcid.org/0000-0003-1418-3576

Role: Formal analysisRole: SoftwareRole: Visualization

Xiaoran Li:

ORCID: https://orcid.org/0000-0002-7438-8920

Role: ConceptualizationRole: MethodologyRole: Resources

Na Niu: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Yan Liu:

ORCID: https://orcid.org/0000-0002-1518-7264

Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Supervision

Richard A. Hajek: Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: Writing - review & editing

Guang Peng:

ORCID: https://orcid.org/0000-0002-4392-1497

Role: ValidationRole: Writing - review & editing

Shannon Westin:

ORCID: https://orcid.org/0000-0002-1922-0156

Role: ConceptualizationRole: Funding acquisitionRole: Writing - review & editing

Anil K. Sood:

ORCID: https://orcid.org/0000-0001-5458-2243

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Validation

Jinsong Liu:

ORCID: https://orcid.org/0000-0002-3239-6658

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: July 2023

Publication date (Electronic, pub): 21 July 2023

Volume: 9

Issue: 29

Electronic Location Identifier: eadf7195

Affiliations

[ ¹ ]Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[ ² ]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[ ³ ]Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[ ⁴ ]Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Author notes

[* ]Corresponding author: Email: jliu@ 123456mdanderson.org (J.L.) ; asood.mdanderson.org (A.K.S.)

Author information

Xudong Zhang https://orcid.org/0000-0003-1896-4898

Jun Yao https://orcid.org/0000-0003-1418-3576

Xiaoran Li https://orcid.org/0000-0002-7438-8920

Yan Liu https://orcid.org/0000-0002-1518-7264

Guang Peng https://orcid.org/0000-0002-4392-1497

Shannon Westin https://orcid.org/0000-0002-1922-0156

Anil K. Sood https://orcid.org/0000-0001-5458-2243

Jinsong Liu https://orcid.org/0000-0002-3239-6658

Article

Publisher ID: adf7195

DOI: 10.1126/sciadv.adf7195

PMC ID: 10361597

PubMed ID: 37478190

SO-VID: 69d836c5-bb21-4401-a5a5-afde6391694d

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 08 November 2022

Date accepted : 21 June 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002387, National Cancer Institute, Cairo University;

Award ID: P50CA217685

Funded by: FundRef http://dx.doi.org/10.13039/501100002387, National Cancer Institute, Cairo University;

Award ID: P30CA016672

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Copyeditor Eunice Ann Alesin

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Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

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Gamma Delta T cells

Most cited references 69

Integrated Genomic Analyses of Ovarian Carcinoma

Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.

PARP inhibitors: Synthetic lethality in the clinic.

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Cited by 9

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