5 years ago

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

High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors
Sylvain Baulande, Elaine Del Nery, Marie-Ming Aynaud, Olivier Delattre, Mylène Bohec, Aurianne Lescure, Laetitia Maillot, Elodie Anthony, Amaury Leruste, Julien Masliah-Planchon, Sakina Zaidi, Sergio Roman-Roman, Stefano Cairo, Wilfrid Richer, Franck Bourdeaut, Didier Surdez, Zhi-Yan Han, Arnault Tauziede-Espariat, Mamy Andrianteranagna, Céline Chauvin


Rhabdoid tumors (RTs) are aggressive tumors 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 of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRα/β and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31539-5

DOI: 10.1016/j.celrep.2017.10.076

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