High-Throughput Drug Screening in Chondrosarcoma Cells Identifies Effective Antineoplastic Agents Independent of IDH Mutation

Abstract

The term chondrosarcoma refers to a rare and heterogeneous group of malignant cartilaginous tumors that are typically resistant to chemotherapy and radiotherapy. Metastatic chondrosarcoma has a poor prognosis, and effective systemic therapies are lacking. Isocitrate dehydrogenase (IDH) mutations represent a potential therapeutic target, but IDH inhibitors alone have shown limited clinical efficacy to date. Although the role of conventional chemotherapy is still subject to debate, some evidence suggests it may provide therapeutic benefits in advanced cases. In this study, we aimed to identify effective compounds for combination therapy in chondrosarcoma. Using high-throughput screening, we evaluated a panel of anticancer agents in IDH1-mutant chondrosarcoma cell lines and their mutant IDH1 knockout derivatives. The top 20 most potent compounds were identified across all cell lines, irrespective of IDH mutation status. Representative drugs selected for further investigation included docetaxel, methotrexate, panobinostat, idarubicin, camptothecin, and pevonedistat. These drugs inhibited colony formation, induced apoptosis and cell cycle arrest, and exhibited synergistic antitumor activity in two-drug combinations. In conclusion, we identified several highly effective agents with potent anti-tumor activity in chondrosarcoma cells, independent of IDH mutation status. These agents represent promising candidates for chondrosarcoma therapy and warrant further preclinical investigation and potential inclusion in clinical trials.