RAD50 Deficient in a Breast Cancer Model Predicts Sensitivity to PARP Inhibitors-Reference-Cited by-同舟云学术

RAD50 Deficient in a Breast Cancer Model Predicts Sensitivity to PARP Inhibitors

Published:2023-12 Issue:11 Volume:23 Page:900-909
ISSN:1568-0096
Container-title:Current Cancer Drug Targets
language:en
Short-container-title:CCDT

Author:

Niederauer Ramos Cíntia Regina¹^ORCID,Silva Oliveira Renato José¹^ORCID,Rosa Marcela Nunes¹^ORCID,Pereira Ariane Stéfani¹^ORCID,de Abreu Renata Barbosa Vahia¹^ORCID,Helvoort Lengert Andre van¹^ORCID,Reis Rui Manuel¹²³^ORCID,Oliveira Silva Viviane Aline¹⁴⁵^ORCID,Palmero Edenir Inêz¹⁶^ORCID,Melendez Matias Eliseo¹⁷^ORCID

Affiliation:

1. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil

2. Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal

3. ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal

4. Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, 40296-710, Bahia, Brazil

5. Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador, 40110-909, Bahia, Brazil

6. Department of Genetics, Brazilian National Cancer Institute, Rio de Janeiro, Brazil

7. Department of Molecular Carcinogenesis, Brazilian National Cancer Institute, Rio de Janeiro, Brazil

Abstract

Background: Breast and ovarian tumors with pathogenic variants in BRCA1 or BRCA2 genes are more sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi) treatment than wildtype tumors. Pathogenic variants in non-BRCA1/2 homologous recombination repair genes (HRR) also concede sensitivity to PARPi treatment. RAD50 participates in the Mre11-Rad50-Nbn (MRN) complex of the HRR pathway and plays an important role in DNA repair. Objective: The objective of this study is to evaluate whether RAD50 protein deficiency modulates the PARPi response in breast cancer cell lines. Methods: T47D breast cancer cell line was modified using small interfering RNA and CRISPR/Cas9 technology, to knockout the RAD50 gene. PARPi response (niraparib, olaparib and rucaparib alone or in combination with carboplatin), in T47D and T47D-edited clones, was evaluated by cell viability, cell cycle, apoptosis and protein expression analyses. Results: Treatment with niraparib and carboplatin exerted a synergistic effect on T47D-RAD50 deficient cells and an antagonistic effect on T47D cells parental. Cell cycle analysis demonstrated an increase in the G2/M population in cells treated with niraparib or rucaparib alone or in combination with carboplatin. T47D-RAD50 deficient cells treated with rucaparib and carboplatin exhibited twofold levels in late apoptosis, also showing differences in PARP activation. All T47D RAD50 deficient clones treated with niraparib or rucaparib combined with carboplatin, or rucaparib alone showed increased levels of H2AX phosphorylation. Conclusions: T47D RAD50 deficient cells treated with PARP inhibitors alone or in combination with carboplatin showed cell cycle arrest in the G2/M phase, leading to death by apoptosis. Thus, RAD50 deficiency may be a good biomarker for predicting PARPi response.

Funder

Brazilian Ministry of Health - PRONON

FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo

Publisher

Bentham Science Publishers Ltd.

Subject

Cancer Research,Drug Discovery,Pharmacology,Oncology

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