Acquisition of resistance to phosphatidylinositol 3-kinase (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-coenzyme A (CoA) shortage, and a global decrease in histone acetylation. In addition, PI3K/AKT inhibitors induce drug resistance by selectively augmenting histone H3 lysine 27 acetylation (H3K27ac) 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 histone deacetylase (HDAC) inhibitors. Little or no 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.

获得对磷脂酰肌醇 3-激酶 (PI3K)/AKT 靶向单一疗法的耐药性意味着存在独立于癌症类型的常见耐药机制。在这里，我们证明 PI3K/AKT 抑制剂会导致糖酵解危机、乙酰辅酶 A (CoA) 短缺和组蛋白乙酰化的全球性下降。此外，PI3K/AKT 抑制剂通过选择性增强组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 和 CBP/p300 和 BRD4 蛋白在生长因子和受体 (GF/R) 基因位点子集上的结合来诱导耐药性。这些位点的 BRD4 占用和耐药细胞生长易受溴结构域和组蛋白去乙酰化酶 (HDAC) 抑制剂的影响。在 GF/R 基因位点几乎没有或没有占据 HDAC 蛋白强调了细胞对具有相反作用模式的两类抑制剂的等效反应这一悖论。针对这种独特的乙酰组蛋白相关脆弱性提供了两种临床上可行的策略来克服不同癌症中的 PI3K/AKT 抑制剂耐药性。