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

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.
Di Wu 1,  Yuqian Yan 2,  Ting Wei 3,  Zhenqing Ye 3,  Yutian Xiao 4,  Yunqian Pan 2,  Jacob J Orme 5,  Dejie Wang 2,  Liguo Wang 6,  Shancheng Ren 7,  Haojie Huang 8
Affiliations

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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.

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