MDM2 is a Promising Synthetic Lethal Candidate for ARID1A‐Mutated Ovarian Clear Cell Carcinoma

Background: Ovarian clear cell carcinoma (OCCC) is a type of ovarian cancer with a poor prognosis if detected in the progressive stage since there is less effective chemotherapy. Recent advancements in molecular-targeted drugs have not substantially affected OCCC treatment. Therefore, we explored the potential of targeting MDM2 in OCCC cells. Methods: We used TOV-21G and KOC7c cells as the ARID1A mutant-type, and RMG-I and ES2 cells as the ARID1A wild-type. Then, we performed small interfering library screening, Western blotting, real-time polymerase chain reaction analysis, cell proliferation assay, cell cycle analysis, time-lapse cell proliferation assessment, and DNA damage assessment. Next, to generate murine intraperitoneal tumors, 7.5 × 106 TOV-21G cells in 200 μL of phosphate-buffered saline were injected subcutaneously into the intraperitoneum in 5–6-week-old athymic nude mice. Results: Using various cell lines with ARID1A mutations or without mutation, the results showed that the interference of MDM2 effectively reduced cell proliferation in ARID1A-mutant cells but not in ARID1A wild-type cells. Additionally, interference with ARID1A against ARID1A wild strains reproduced susceptibility to MDM2 interference. In vivo experiments demonstrated that nutlin-3, an MDM2 inhibitor, significantly suppressed tumor growth in the ovarian cancer mouse model. Conclusion: These findings suggest that targeting MDM2 may be a viable strategy for the treat-ment of ARID1A-mutated OCCC, offering a new therapeutic approach for this challenging type of cancer.