Targeting the GSK-3β/mTOR axis to overcome chemoresistance in gestational choriocarcinoma: molecular mechanisms and therapeutic opportunities.

Gestational choriocarcinoma represents one of the most curable solid tumors when diagnosed early, with cure rates exceeding 95% using standard chemotherapy. However, a subset of patients develops chemoresistance, leading to treatment failure and poor outcomes. Emerging evidence indicates that aberrant activation of the glycogen synthase kinase-3β (GSK-3β)/mechanistic target of rapamycin (mTOR) signaling axis is strongly associated with chemoresistance through multiple interconnected mechanisms. This review examines the molecular pathways by which GSK-3β and mTOR likely contribute to chemoresistance in gestational choriocarcinoma, including enhanced epithelial-mesenchymal transition (EMT), metabolic reprogramming, immune evasion, autophagy dysregulation, and suppression of apoptosis. We analyze how crosstalk between GSK-3β and mTOR complexes (mTORC1/mTORC2) creates a resistant phenotype that limits the efficacy of conventional cytotoxic agents such as methotrexate, actinomycin D, and etoposide. Importantly, we highlight emerging therapeutic strategies to target this axis, including GSK-3β activators (lithium, 9-ING-41), mTOR inhibitors (rapamycin analogs, dual PI3K/mTOR inhibitors), and combination regimens that synergistically restore chemosensitivity. Preclinical data from trophoblastic and related malignancies demonstrate that dual targeting of GSK-3β and mTOR can reverse resistance phenotypes and enhance treatment responses. This comprehensive review provides a translational framework for developing molecularly targeted therapies in chemoresistant gestational choriocarcinoma, with potential implications for personalized treatment algorithms and clinical trial design in this rare but highly treatable malignancy.