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

doi:10.1016/j.celrep.2021.108744

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

Cell Rep. 2021 Feb 16;34(7):108744. doi: 10.1016/j.celrep.2021.108744.

Authors

Di Wu¹, Yuqian Yan², Ting Wei³, Zhenqing Ye³, Yutian Xiao⁴, Yunqian Pan², Jacob J Orme⁵, Dejie Wang², Liguo Wang⁶, Shancheng Ren⁷, Haojie Huang⁸

Affiliations

¹ Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Wuxi Institute of Health Sciences of Beijing Institute of Genomics, Wuxi 214174, China.
² Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA.
³ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
⁴ Department of Urology, Shanghai Changhai Hospital, Shanghai 200433, China.
⁵ Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
⁶ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA. Electronic address: wang.liguo@mayo.edu.
⁷ Wuxi Institute of Health Sciences of Beijing Institute of Genomics, Wuxi 214174, China; Department of Urology, Shanghai Changhai Hospital, Shanghai 200433, China. Electronic address: renshancheng@gmail.com.
⁸ Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, MN 55905, USA. Electronic address: huang.haojie@mayo.edu.

PMID: 33596421
DOI: 10.1016/j.celrep.2021.108744

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm
HCT116 Cells
Histone Deacetylase Inhibitors / pharmacology*
Histones / metabolism*
Humans
Male
Mice
Mice, SCID
Neoplasms / drug therapy*
Neoplasms / enzymology
Neoplasms / metabolism
Nerve Tissue Proteins / antagonists & inhibitors*
Nerve Tissue Proteins / metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Receptors, Cell Surface / antagonists & inhibitors*
Receptors, Cell Surface / metabolism
Xenograft Model Antitumor Assays

Substances

Dner protein, mouse
Histone Deacetylase Inhibitors
Histones
Nerve Tissue Proteins
Phosphoinositide-3 Kinase Inhibitors
Receptors, Cell Surface
Proto-Oncogene Proteins c-akt