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Int. J. Mol. Sci. 2017, 18(7), 1537; doi:10.3390/ijms18071537

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors

1
University Children’s Hospital Muenster, Department of Pediatric Hematology and Oncology, 48149 Münster, Germany
2
Children’s Hospital and Swabian Children’s Cancer Center, 86156 Augsburg, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 30 May 2017 / Revised: 11 July 2017 / Accepted: 13 July 2017 / Published: 16 July 2017
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Abstract

Rhabdoid tumors (RT) are malignant neoplasms of early childhood. Despite intensive therapy, survival is poor and new treatment approaches are required. The only recurrent mutations in these tumors affect SMARCB1 and less commonly SMARCA4, both subunits of the chromatin remodeling complex SWItch/Sucrose Non-Fermentable (SWI/SNF). Loss of these two core subunits alters the function of the SWI/SNF complex, resulting in tumor development. We hypothesized that inhibition of aberrant SWI/SNF function by selective blockade of the BRD9 subunit of the SWI/SNF complex would reduce tumor cell proliferation. The cytotoxic and anti-proliferative effects of two specific chemical probes (I-BRD9 and BI-9564) which target the bromodomain of SWI/SNF protein BRD9 were evaluated in 5 RT cell lines. Combinatorial effects of I-BRD9 and cytotoxic drugs on cell proliferation were evaluated by cytotoxicity assays. Single compound treatment of RT cells with I-BRD9 and BI-9564 resulted in decreased cell proliferation, G1-arrest and apoptosis. Combined treatment of doxorubicin or carboplatin with I-BRD9 resulted in additive to synergistic inhibitory effects on cell proliferation. In contrast, the combination of I-BRD9 with vincristine demonstrated the antagonistic effects of these two compounds. We conclude that the BRD9 bromodomain is an attractive target for novel therapies in this cancer. View Full-Text
Keywords: rhabdoid tumor; BRD9; SWI/SNF complex; targeted therapy rhabdoid tumor; BRD9; SWI/SNF complex; targeted therapy
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MDPI and ACS Style

Krämer, K.F.; Moreno, N.; Frühwald, M.C.; Kerl, K. BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors. Int. J. Mol. Sci. 2017, 18, 1537.

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