Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors
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Natalia Moreno1,2,*, Till Holsten1,*, Julius Mertins1, Annabelle Zhogbi1, Pascal Johann3, Marcel Kool3, Michael Meisterernst1 and Kornelius Kerl1,2
1Institute of Molecular Tumor Biology, Westfalian Wilhelms University, Muenster, Germany
2University Children’s Hospital Muenster, Department of Pediatric Hematology and Oncology, Muenster, Germany
3Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
*These authors have contributed equally to this work
Kornelius Kerl, email: [email protected]
Keywords: CDK9, BRD4, rhabdoid tumors, synergistic, SMARCB1
Received: January 18, 2017 Accepted: June 01, 2017 Published: June 21, 2017
Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds. Combination of both compounds efficiently represses antiapoptotic genes and the oncogene MYC. Our results provide a novel approach for the treatment of RT.
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