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

Mylène Bohec, Franck Bourdeaut, Elaine Del Nery, Olivier Delattre, Sergio Roman-Roman, Stefano Cairo, Julien Masliah-Planchon, Laetitia Maillot, Marie-Ming Aynaud, Sakina Zaidi, Céline Chauvin, Sylvain Baulande, Wilfrid Richer, Elodie Anthony, Zhi-Yan Han, Aurianne Lescure, Didier Surdez, Mamy Andrianteranagna, Arnault Tauziede-Espariat, Amaury Leruste

Journal: Cell reports 2018;21(7):1737-1745

PMID: 29141209

Free Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: Paris-Sciences-Lettres Research University, Institut Curie Research Center, SiRIC, Laboratory of Translational Research in Pediatric Oncology, Paris 75005, France; Paris-Sciences-Lettres Research University, Institut Curie Research Center, INSERM U830, Laboratory of Biology and Genetics of Cancers, Paris 75005, France.; Sainte-Anne Hospital, Department of Neuropathology, Paris 75005, France.; Paris-Sciences-Lettres Research University, Institut Curie Research Center, INSERM U830, Laboratory of Biology and Genetics of Cancers, Paris 75005, France.; Paris-Sciences-Lettres Research University, Institut Curie, Department of Translational Research, the Biophenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris 75005, France.; Paris-Sciences-Lettres Research University, Institut Curie, Next Generation Sequencing Platform, Paris 75005, France.; Paris-Sciences-Lettres Research University, Institut Curie, Laboratory of Somatic Genetics, Paris 75005, France.; LTTA Center, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy; XenTech, Evry 91000, France.; Paris-Sciences-Lettres Research University, Institut Curie Research Center, SiRIC, Laboratory of Translational Research in Pediatric Oncology, Paris 75005, France; Paris-Sciences-Lettres Research University, Institut Curie Research Center, INSERM U830, Laboratory of Biology and Genetics of Cancers, Paris 75005, France; Paris-Sciences-Lettres Research University, Institut Curie, Laboratory of Somatic Genetics, Paris 75005, France.; Paris-Sciences-Lettres Research University, Institut Curie Research Center, SiRIC, Laboratory of Translational Research in Pediatric Oncology, Paris 75005, France; Paris-Sciences-Lettres Research University, Institut Curie Research Center, INSERM U830, Laboratory of Biology and Genetics of Cancers, Paris 75005, France; Paris-Sciences-Lettres Research University, Institut Curie Hospital, Department of Pediatric Oncology- Adolescents and Young Adults, Paris 75005, France. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2017.10.076

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MeSH Terms: Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Drug Discovery, Endoplasmic Reticulum Stress, High-Throughput Screening Assays, Humans, Indazoles, Protein Kinase Inhibitors, Pyrimidines, Quaternary Ammonium Compounds, Receptor, Platelet-Derived Growth Factor alpha, Receptor, Platelet-Derived Growth Factor beta, Rhabdoid Tumor, SMARCB1 Protein, Sulfonamides