An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors

Di Wu, Yuqian Yan, Ting Wei, Zhenqing Ye, Yutian Xiao, Yunqian Pan, Jacob J. Orme, Dejie Wang, Liguo Wang, Shancheng Ren, Haojie Huang

Research output: Contribution to journalArticlepeer-review

Abstract

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. Acquisition of resistance to PI3K/AKT-targeted monotherapy regardless of cancer type implies the existence of common mechanisms. Wu et al. identify an intrinsic mechanism that not only drives PI3K/AKT inhibitor resistance but also can be vulnerably targeted paradoxically by both BET and HDAC inhibitors.

Original languageEnglish (US)
Article number108744
JournalCell reports
Volume34
Issue number7
DOIs
StatePublished - Feb 16 2021

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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