AZD5153 reverses palbociclib resistance in ovarian cancer by inhibiting cell cycle-related proteins and the MAPK/PI3K-AKT pathway.
Cancer Lett
; 528: 31-44, 2022 03 01.
Article
en En
| MEDLINE
| ID: mdl-34942306
ABSTRACT
The CDK4/6 inhibitor, palbociclib has recently entered clinic-trial stage for breast cancer treatment. However, translating its efficacy to other solid tumors has been challenging, especially for aggressive solid tumors. We found that the effect of palbociclib as a single agent was limited due to primary and acquired resistance in multiple ovarian cancer (OC) models. Among these, patient-derived organoid and xenograft models are two most representative models of drug responsiveness in patients with OC. In preclinical models, this study demonstrated that activated MAPK/PI3K-AKT pathway and cell cycle-related proteins induced the resistance to palbociclib, which was overcome by the addition of the bromodomain protein 4 (BRD4) inhibitor AZD5153. Moreover, this study revealed that AZD5153 and palbociclib had a synergistic lethal effect on inducing the cell cycle arrest and increasing apoptosis, even in RB-deficient cell lines. Based on these results, it is anticipated that this class of drugs, including AZD5153, which inhibit the cell cycle-related protein and MAPK/PI3K-AKT pathway, will exhibit synergistic effects with palbociclib in OC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
/
Piperazinas
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Pirazoles
/
Piridazinas
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Piridinas
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Proteínas de Ciclo Celular
/
Fosfatidilinositol 3-Quinasas
/
Quinasas de Proteína Quinasa Activadas por Mitógenos
/
Proteínas Proto-Oncogénicas c-akt
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Cancer Lett
Año:
2022
Tipo del documento:
Article
País de afiliación:
China