Abstract 1730: Onvansertib in combination with carboplatin demonstrates enhanced anti-tumorigenic effects in pre-clinical models of serous endometrial cancer

Abstract Objectives: Polo-like kinase 1 (PLK1) has key roles in regulating cell division and DNA damage responses, among other critical cellular functions. It is overexpressed in many cancers including endometrial cancer (EC). Onvansertib is a highly selective PLK1 inhibitor that has shown synergistic effects combined with chemotherapy in preclinical models of multiple solid tumors, and combination therapy is currently being evaluated in phase I/II clinical trials of breast and colon cancer. Serous endometrial cancer is an aggressive subtype of EC with a poor prognosis. The backbone adjuvant treatment consists of a platinum-based doublet. We aimed to investigate the effects of onvansertib in combination with carboplatin on cell proliferation, cellular stress, apoptosis, and cellular adhesion and migration in serous EC cell lines. Methods: The human serous EC cell lines, ARK1 and SPEC2, were treated with both onvansertib and carboplatin, alone and in combination. Cell proliferation was evaluated by MTT and colony formation assays. Cellular stress was evaluated by measuring levels of reactive oxygen species (ROS) via DCFH-DA assay and change in mitochondrial membrane potential via JC-1 assay. Apoptosis was evaluated using cleaved caspace-3 assay. Cell adhesion was evaluated using laminin-1 assay, and cell migration was assessed by wound healing assay. Western immunoblotting was used to measure downstream protein expression related to cell cycle progression, cellular invasion, and apoptosis. Results: Onvansertib and carboplatin both inhibited the proliferation and colony formation of ARK1 and SPEC2 cells, and combined treatment produced a synergistic response (CI<1). Combination treatment with onvansertib and carboplatin of serous endometrial cancer cells resulted in significantly higher levels of ROS production (p<0.05) and decreased mitochondrial membrane potential (p<0.01) relative to single-agent treatment. Onvansertib combined with carboplatin also significantly increased the activity of cleaved caspase-3 compared with single-agent treatment (p<0.05). Importantly, compared to each single-drug treatment, combination treatment impeded cell migration (scratch closure) and significantly decreased cell adhesion (laminin assay) in the ARK1 and SPEC2 cell lines (all p<0.05). Western immunoblotting supported these results, showing combination treatment resulted in downregulation of cell cycle regulatory proteins CDK2, CDK4, and cyclin D1 and the EMT markers SLUG and beta-catenin, and upregulation of the pro-apoptotic protein Bax. Conclusions: The combination of onvansertib and carboplatin demonstrated potent anti-tumorigenic effects in serous EC cells compared with onvansertib or carboplatin alone. Further studies are warranted to evaluate if this combination may translate into a novel clinical therapeutic option for serous EC. Citation Format: Glenn P. Boyles, Haomeng Zhang, Chelsey Vranes, Michael Emanuele, Chunxiao Zhou, Victoria Bae-Jump. Onvansertib in combination with carboplatin demonstrates enhanced anti-tumorigenic effects in pre-clinical models of serous endometrial 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 1730.