Abstract 4452: Targeting matrix metalloproteinase-3 to reverse chemotherapy resistance in high-grade serous ovarian cancer

Abstract High-Grade Serous Ovarian Cancer (HGSOC) remains the most aggressive and lethal gynecological malignancy, with most patients developing resistance to platinum-based chemotherapies. Matrix Metalloproteinase-3 (MMP3), an enzyme involved in extracellular matrix remodeling, has been implicated in this resistance. Prior work in our lab demonstrated that MMP3 is overexpressed in chemotherapy-resistant ovarian cancer cell lines, including the cisplatin resistant cells, OVCAR3CIS and A2780CP20, compared to their sensitive counterparts, OVCAR3 and A2780, respectively. Our team previously showed that knockdown of MMP3 with small interference RNA (siRNA) reduce cell growth and invasion of cisplatin-resistant ovarian cancer cells. We have progressed toward therapeutic applications by developing small molecule inhibitors (SMIs) to target MMP3. Bioinformatics was used to select potential MMP3 inhibitor candidates starting with a library of 370,000 compounds. Cell viability assays showed that four out of 30 preselected SMIs significantly reduced cell viability in cisplatin resistant cell lines. Further evaluation in combination therapy revealed promising results, as pre-treating cisplatin-resistant HGSOC cells with SMIs resensitized the cells to cisplatin treatment. These findings provide compelling evidence that MMP3 inhibition can restore chemotherapy sensitivity in resistant HGSOC cells, offering a promising dual-therapy approach. This research represents a significant advancement in developing novel therapeutic strategies to overcome chemotherapy resistance and improve outcomes for HGSOC patients. Citation Format: Víctor G. Reyes-Burgos, Marienid Flores-Colón, Eliud Hernández-O’Farrill, Luis E. Vázquez-Quiñones, Pablo E. Vivas-Mejía. Targeting matrix metalloproteinase-3 to reverse chemotherapy resistance in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4452.