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.
BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors / E. Derenzini, P. Mondello, T. Erazo, A. Portelinha, Y. Liu, M. Scallion, Z. Asgari, J. Philip, P. Hilden, D. Valli, A. Rossi, H. Djaballah, O. Ouerfelli, E. de Stanchina, V.E. Seshan, R.C. Hendrickson, A. Younes. - In: CELL REPORTS. - ISSN 2211-1247. - 24:8(2018 Aug), pp. 2155-2166.
|Titolo:||BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors|
|Parole Chiave:||BET inhibitor; diffuse large B cell lymphoma; DLBCL; GSK3β; JQ1; lymphoma; MYC; PI3K; Animals; Glycogen Synthase Kinase 3 beta; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Nerve Tissue Proteins; Phosphatidylinositol 3-Kinases; Receptors, Cell Surface|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||ago-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.celrep.2018.07.055|
|Appare nelle tipologie:||01 - Articolo su periodico|