In summary, our work identifies RB protein as a bono fide endogenous inhibitor of BRD4 and demonstrates that RB loss or phosphorylation at S249/T252 by CDK4/6 confers PCa cell resistance to small molecule BET inhibitors by upregulating GNB1L expression and activating GNB1L-CREB signaling cascade. This evidence concerns the gene CDK4 and posterior cortical atrophy.