Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors

// Natalia Moreno 1, 2, * , Till Holsten 1, * , Julius Mertins 1 , Annabelle Zhogbi 1 , Pascal Johann 3 , Marcel Kool 3 , Michael Meisterernst 1 and Kornelius Kerl 1, 2 1 Institute of Molecular Tumor Biology, Westfalian Wilhelms University, Muenster, Germany 2 University Children’s Hospital Muenster, Department of Pediatric Hematology and Oncology, Muenster, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany * These authors have contributed equally to this work Correspondence to: Kornelius Kerl, email: Kornelius.Kerl@ukmuenster.de Keywords: CDK9, BRD4, rhabdoid tumors, synergistic, SMARCB1 Received: January 18, 2017      Accepted: June 01, 2017      Published: June 21, 2017 ABSTRACT 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.