Trabectedin Induces Synthetic Lethality via the p53-Dependent Apoptotic Pathway in Ovarian Cancer Cells Without BRCA...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epithelial ovarian cancer (EOC) remains a significant health challenge.
• BRCA-proficient EOC presents unique therapeutic resistance.
• Targeting DNA repair pathways offers potential for synthetic lethality.

Purpose of the Study:

• To investigate the synergistic effects of niraparib and trabectedin in BRCA-proficient EOC.
• To determine if the combination induces DNA repair deficiencies and synthetic lethality.
• To elucidate the role of p53 in the observed therapeutic response.

Main Methods:

• Cell viability assays (CCK-8) were performed on A2780 and SKOV3 cell lines.
• Gene expression analysis (RT-qPCR, Western blot) assessed DNA repair and apoptosis markers.
• Apoptosis was quantified using Annexin V/PI staining.
• p53 silencing was achieved via siRNA to assess its role.

Main Results:

• Combination therapy showed synergistic cytotoxicity in A2780 cells, but not SKOV3 cells.
• Treatment downregulated key DNA repair proteins (BRCA1, BRCA2, RAD51, PARP1/2) and increased DNA damage markers (γ-H2AX).
• The combination upregulated pro-apoptotic factors and cell cycle inhibitors (p53, PUMA, NOXA, BAX, BAK, p21), inducing p53-mediated apoptosis and cell cycle arrest.
• p53 silencing abrogated the synergistic effects, confirming its critical role.

Conclusions:

• Niraparib and trabectedin combination therapy effectively impairs DNA repair in BRCA-proficient EOC.
• This impairment leads to synthetic lethality via p53-dependent apoptosis.
• The findings suggest a promising therapeutic strategy for specific ovarian cancer subtypes.