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BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors

Enrico Derenzini1, Patrizia Mondello2, Tatiana Erazo2

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Oncohematology Unit, European Institute of Oncology, Milan, Italy.

Cell Reports
|August 23, 2018
PubMed

Insights

Bromodomain and extraterminal protein family inhibitors (BETi) combined with PI3K inhibitors show promise for lymphoma treatment. BETi enhance anti-cancer effects by regulating GSK3β and β-catenin pathways, offering new combination strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The PI3K-GSK3β axis is crucial in MYC-driven lymphomagenesis.
  • MYC-targeting BET inhibitors are a potential lymphoma treatment.

Purpose of the Study:

  • To investigate the combinatorial effects of BET inhibitors and PI3K inhibitors in lymphoma.
  • To elucidate the molecular mechanisms underlying BET inhibitor-induced prosurvival feedbacks.

Main Methods:

  • High-throughput drug screening of lymphoma cell lines.
  • MYC silencing and gene expression analysis.
  • Western blotting for protein phosphorylation and abundance.
  • Mouse xenograft models for diffuse large B cell lymphoma (DLBCL).

Main Results:

  • BET inhibitors synergize with PI3K inhibitors to reduce lymphoma cell proliferation.
  • BETi upregulate PI3K pathway genes and increase GSK3β S9 phosphorylation, leading to elevated β-catenin.
  • BETi downregulate UBE2C and UBE2T, contributing to GSK3β S9 phosphorylation and β-catenin stabilization.
  • In vivo, BETi decrease MYC, UBE2C, UBE2T, and increase phospho-GSK3β S9, enhancing PI3K inhibitor efficacy.

Conclusions:

  • BET inhibitors induce prosurvival feedbacks via GSK3β regulation in lymphoma.
  • This study provides a mechanistic basis for combining BET inhibitors and PI3K inhibitors in lymphoma therapy.
Keywords:
BET inhibitorDLBCLGSK3βJQ1MYCPI3Kdiffuse large B cell lymphomalymphoma

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