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

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

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

Author(s) -

Enrico Derenzini,

Patrizia Mondello,

Tatiana Erazo,

Ana Portelinha,

Yuxuan Liu,

Mary I. Scallion,

Zahra Asgari,

John Philip,

Patrick Hilden,

Debora Valli,

Alessandra Rossi,

Hakim Djaballah,

Ouathek Ouerfelli,

Elisa de Stanchina,

Venkatraman Seshan,

Ronald C. Hendrickson,

Anas Younes

Publication year - 2018

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2018.07.055

Subject(s) - pi3k/akt/mtor pathway , gsk 3 , gene silencing , cancer research , protein kinase b , lymphoma , gsk3b , phosphorylation , biology , small interfering rna , chemistry , microbiology and biotechnology , signal transduction , cell culture , gene , biochemistry , genetics , transfection , immunology

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.

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