Synergistic anti-tumor effect of combining selective CDK7 and BRD4 inhibition in MYCN-amplified neuroblastoma

Cyclin-dependent kinases (CDKs) that have critical roles in RNA polymerase II (Pol II)-mediated gene transcription are emerging as therapeutic targets in cancer. We have previously shown that THZ1, a covalent inhibitor of CDKs7/12/13, leads to cytotoxicity in MYCN-amplified neuroblastoma through the downregulation of super-enhancer-associated transcriptional upregulation. We sought to dissect the mechanisms of cytotoxicity in NB cells and to identify additional targets that could be inhibited together with CDK7 in combination therapy. Overall design: RNA-Seq in human neuroblastoma cells treated with CDK7 inhibitor (YKL-5-124), BRD4 inhibitor (JQ1) or both. DMSO treated cells were used as control.