Targeting HSP90 with Ganetespib to Induce CDK1 Degradation and Promote Cell Death in Hepatoblastoma.
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BACKGROUND/OBJECTIVES: Hepatoblastoma, the most common malignant liver tumor in pediatric patients, is characterized by a remarkably low mutation rate, thereby impeding targeted therapies. Current treatment regimens rely on conventional cytotoxic agents that often cause severe adverse effects, necessitating the search for novel, less toxic therapeutic approaches. METHODS: In this study, we explored the anti-tumor potential of heat shock protein 90 (HSP90) inhibitors using a unique collection of hepatoblastoma in vitro models. RESULTS: Among the five tested inhibitors, we identified ganetespib as the most effective, significantly suppressing tumor cell growth while sparing healthy, non-tumor cells. Ganetespib treatment at low nanomolar concentrations markedly reduced cell proliferation, impaired long-term survival, and inhibited three-dimensional spheroid growth, ultimately leading to the induction of apoptosis. Mechanistically, ganetespib downregulated the expression of the HSP90 client protein cyclin-dependent kinase 1, a key cell cycle regulator controlling G2/M phase transition, which is heavily upregulated in hepatoblastoma. This disruption consequently resulted in cell cycle arrest, further contributing to its anti-tumor effects. CONCLUSIONS: HSP90 inhibition by ganetespib demonstrates significant potential as a novel therapeutic strategy for hepatoblastoma, offering a potential alternative to current cytotoxic treatments with fewer adverse effects.