An acetyl-histone vulnerability in PI3K/AKT inhibition resistant cancers is targetable by both BET and HDAC inhibitors
Acquisition of resistance to PI3K/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-CoA shortage and a global decrease in histone acetylation. Also, PI3K/AKT inhibitors induce drug resistance by selectively augmenting H3K27 acetylation and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique acetyl-histone related vulnerability offers two clinically viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.