BET Inhibition-Induced GSK3? Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors.

ABSTRACT: The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase ? (GSK3?) 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 GSK3? S9 inhibitory phosphorylation, resulting in increased ?-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3? S9 phosphorylation levels and ?-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-GSK3? S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3? regulation, providing a mechanistic rationale for combination strategies.

SUBMITTER: Derenzini E 

PROVIDER: S-EPMC7456333 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature