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

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

doi:10.1016/j.celrep.2017.10.076

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

Cell Rep. 2017 Nov 14;21(7):1737-1745. doi: 10.1016/j.celrep.2017.10.076.

Authors

Céline Chauvin¹, Amaury Leruste¹, Arnault Tauziede-Espariat², Mamy Andrianteranagna¹, Didier Surdez³, Aurianne Lescure⁴, Zhi-Yan Han¹, Elodie Anthony⁴, Wilfrid Richer¹, Sylvain Baulande⁵, Mylène Bohec⁵, Sakina Zaidi³, Marie-Ming Aynaud³, Laetitia Maillot⁶, Julien Masliah-Planchon⁶, Stefano Cairo⁷, Sergio Roman-Roman⁴, Olivier Delattre⁸, Elaine Del Nery⁴, Franck Bourdeaut⁹

Affiliations

¹ 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.
² Sainte-Anne Hospital, Department of Neuropathology, Paris 75005, France.
³ Paris-Sciences-Lettres Research University, Institut Curie Research Center, INSERM U830, Laboratory of Biology and Genetics of Cancers, Paris 75005, France.
⁴ 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.
⁵ Paris-Sciences-Lettres Research University, Institut Curie, Next Generation Sequencing Platform, Paris 75005, France.
⁶ Paris-Sciences-Lettres Research University, Institut Curie, Laboratory of Somatic Genetics, Paris 75005, France.
⁷ LTTA Center, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy; XenTech, Evry 91000, France.
⁸ 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.
⁹ 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].

PMID: 29141209
DOI: 10.1016/j.celrep.2017.10.076

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.

Keywords: SMARCB1; clofilium tosylate; high-throughput drug screening; pazopanib; rhabdoid tumors; tyrosine kinase inhibitors.

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Drug Discovery / methods*
Endoplasmic Reticulum Stress / drug effects
High-Throughput Screening Assays / methods*
Humans
Indazoles
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / pharmacology*
Quaternary Ammonium Compounds / pharmacology*
Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
Rhabdoid Tumor / metabolism*
SMARCB1 Protein / metabolism
Sulfonamides / pharmacology*

Substances

Antineoplastic Agents
Indazoles
Protein Kinase Inhibitors
Pyrimidines
Quaternary Ammonium Compounds
SMARCB1 Protein
SMARCB1 protein, human
Sulfonamides
pazopanib
clofilium
Receptor, Platelet-Derived Growth Factor alpha
Receptor, Platelet-Derived Growth Factor beta