Bromodomain and HDAC inhibitors equivalently overcome PI3K/AKT inhibition resistance in cancers
Blocking BRD4 or HDACs induces paradoxically similar gene expression, comparably attenuates PI3K/AKT inhibitor resistance in multiple cancer cells. PI3K/AKT inhibitors induce global loss of histone acetylation. While in the resistant cells, specific genome loci gain H3K27 acetylation and BRD4 binding coupled with up-regulation of selective genes. These loci and genes are vulnerable to BRD4 or CBP/p300 bromodomain inhibitors, as well as HDAC inhibitors. Inadequate occupancy of HDACs on these loci permits gain of H3K27 acetylation and BRD4 recruitment after AKT inhibition. Bromodomain inhibitors directly suppress these loci; HDAC inhibitors induce histone hyper-acetylation outside these loci, offering competitive BRD4 binding sites, re-localizing BRD4. To suppress these loci, genes, and relative resistance, multi-bromodomain inhibitor NEO2734 and HDAC inhibitors are equivalent in effects.