Your browser doesn't support javascript.
loading
Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer.
Liang, Jianqiang; Zhou, Xuan; Yuan, Lin; Chen, Tian; Wan, Yicong; Jiang, Yi; Meng, Huangyang; Xu, Mengting; Zhang, Lin; Cheng, Wenjun.
Afiliación
  • Liang J; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Zhou X; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Yuan L; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Chen T; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Wan Y; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Jiang Y; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Meng H; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Xu M; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Zhang L; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • Cheng W; Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
Int J Biol Sci ; 20(11): 4513-4531, 2024.
Article en En | MEDLINE | ID: mdl-39247812
ABSTRACT
Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Ftalazinas / Piperazinas / Inestabilidad Genómica Límite: Animals / Female / Humans Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Ftalazinas / Piperazinas / Inestabilidad Genómica Límite: Animals / Female / Humans Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia