Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer (TNBC) to DNA holliday junctions.
Biochem Pharmacol
; 225: 116310, 2024 07.
Article
em En
| MEDLINE
| ID: mdl-38788960
ABSTRACT
Targeting the DNA damage response (DDR) is a promising strategy in oncotherapy, as most tumor cells are sensitive to excess damage due to their repair defects. Ataxia telangiectasia mutated and RAD3-related protein (ATR) is a damage response signal transduction sensor, and its therapeutic potential in tumor cells needs to be precisely investigated. Herein, we identified a new axis that could be targeted by ATR inhibitors to decrease the DNA-dependent protein kinase catalytic subunit (DNAPKcs), downregulate the expression of the retinoblastoma (RB), and drive G1/S-phase transition. Four-way DNA Holliday junctions (FJs) assembled in this process could trigger S-phase arrest and induce lethal chromosome damage in RB-positive triple-negative breast cancer (TNBC) cells. Furthermore, these unrepaired junctions also exerted toxic effects to RB-deficient TNBC cells when the homologous recombination repair (HRR) was inhibited. This study proposes a precise strategy for treating TNBC by targeting the DDR and extends our understanding of ATR and HJ in tumor treatment.
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Base de dados:
MEDLINE
Assunto principal:
DNA Cruciforme
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Neoplasias de Mama Triplo Negativas
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Proteínas Mutadas de Ataxia Telangiectasia
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2024
Tipo de documento:
Article