Regorafenib-Induced Stress Response Alters the Bioenergetic Profile of Osteosarcoma Cells and Modulates Gene Expression Associated with Metabolic regulation-a Potential Mechanism of Osteosarcoma Treatment-Related Adaptation.

Purpose: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Despite advances in surgery and multiagent chemotherapy, outcomes remain poor for patients with metastatic or recurrent disease. Regorafenib, an oral multikinase inhibitor targeting pathways involved in tumor proliferation, angiogenesis, and metastasis, has shown clinical promise in osteosarcoma; however, its mechanisms of action are not fully understood. Methods: We investigated the effects of regorafenib in a human osteosarcoma cell line (MG63) and a patient-derived primary cell line (APR1). Cells were treated at their respective IC Results: Regorafenib significantly reduced cell viability, migration, and invasion and induced apoptosis in both cell models. MG63 cells exhibited greater sensitivity, reflected by a lower IC Conclusion: These findings demonstrate the multifaceted antitumor activity of regorafenib in osteosarcoma and highlight cell context-dependent responses. The study provides new insights into molecular and metabolic mechanisms underlying regorafenib activity and supports further investigation of this agent in osteosarcoma therapy.