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

Enrico Derenzini, Patrizia Mondello, Tatiana Erazo, Ana Portelinha, Yuxuan Liu, Mary Scallion, Zahra Asgari, John Philip, Patrick Hilden, Debora Valli, Alessandra Rossi, Hakim Djaballah, Ouathek Ouerfelli, Elisa de Stanchina, Venkatraman E. Seshan, Ronald C. Hendrickson, Anas Younes

Research output: Contribution to journalArticle

Abstract

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase β (GSK3β) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3β S9 inhibitory phosphorylation, resulting in increased β-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3β S9 phosphorylation levels and β-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3β S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3β regulation, providing a mechanistic rationale for combination strategies. In this study, Derenzini et al. demonstrate that BET inhibitors enhance lymphoma vulnerability to PI3K inhibitors by inducing GSK3β feedback in a MYC-dependent manner and by downregulating E2-ubiquitin conjugating enzymes, which further enhance the feedback. These data provide the rationale for combining BET and PI3K inhibitors in lymphoma therapy.

Original languageEnglish
Pages (from-to)2155-2166
Number of pages12
JournalCell Reports
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 21 2018

Keywords

  • BET inhibitor
  • diffuse large B cell lymphoma
  • DLBCL
  • GSK3β
  • JQ1
  • lymphoma
  • MYC
  • PI3K

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Derenzini, E., Mondello, P., Erazo, T., Portelinha, A., Liu, Y., Scallion, M., Asgari, Z., Philip, J., Hilden, P., Valli, D., Rossi, A., Djaballah, H., Ouerfelli, O., de Stanchina, E., Seshan, V. E., Hendrickson, R. C., & Younes, A. (2018). BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors. Cell Reports, 24(8), 2155-2166. https://doi.org/10.1016/j.celrep.2018.07.055