Our data also reveal that depletion of RB enhances BRD4 occupancy at the loci of cancer-related genes including the GPCR-cAMP signaling gene GNB1L. Finally, we demonstrate that loss of RB protein confers resistance to small molecule BET inhibitor and this effect is abolished by co-inhibition of GNB1L-CREB signaling. The gene discussed is BRD4; the disease is cancer.