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

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 and less commonly , both subunits of the chromatin remodeling complex SWItch/Sucrose Non-Ferment...

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Published in:	International journal of molecular sciences Vol. 18; no. 7; p. 1537
Main Authors:	Krämer, Katja F, Moreno, Natalia, Frühwald, Michael C, Kerl, Kornelius
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI 16-07-2017 MDPI AG
Subjects:	Benzylamines BRD9 Carboplatin - pharmacology Carboplatin - therapeutic use Cell Cycle - drug effects Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Cytostatic Agents - therapeutic use Doxorubicin - pharmacology Doxorubicin - therapeutic use Drug Synergism Humans Inhibitory Concentration 50 Naphthyridines rhabdoid tumor Rhabdoid Tumor - drug therapy Rhabdoid Tumor - pathology Small Molecule Libraries - pharmacology Small Molecule Libraries - therapeutic use SWI/SNF complex targeted therapy Vincristine - pharmacology Vincristine - therapeutic use targeted therapy rhabdoid tumor BRD9 SWI/SNF complex
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Summary:	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 and less commonly , 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1422-0067 1422-0067
DOI:	10.3390/ijms18071537