High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors.

摘要: Summary Rhabdoid tumors (RTs) are aggressive of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening approved drugs and identified broad inhibitors tyrosine kinase receptors (RTKs), including pazopanib, the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were PDGFRα/β FGFR2, which most highly expressed RTKs in set primary tumors. Combined genetic inhibition both these only partially recapitulated effect emphasizing requirement for inhibition. CfT perturbed protein metabolism endoplasmic reticulum stress and, combination with induced apoptosis RT cells in vitro . In vivo , reduction tumor growth pazopanib was enhanced CfT, matching efficiency conventional chemotherapy. These results strongly support testing pazopanib/CfT therapy future clinical trials RTs.