Induction of MNK Kinase-dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors.

ABSTRACT: BET inhibitors (BETi), which target transcription of key oncogenic genes, are currently being evaluated in early-phase clinical trials. However, because BETis show limited single-agent activity, there is increasing interest in identifying signaling pathways to enhance the efficacy of BETis. Here, we demonstrate increased MNK kinase-dependent eIF4E phosphorylation following treatment with BETis, indicating activation of a prosurvival feedback mechanism in response to BETis. BET PROTACs, which promote degradation of BET proteins, also induced eIF4E phosphorylation in cancer cells. Mechanistically, we show that the effect of BETis on MNK-eIF4E phosphorylation was mediated by p38 MAPKs. We also show that BETis suppressed RacGAP1 to induce Rac signaling-mediated eIF4E phosphorylation. Significa

SUBMITTER: Pham TND 

PROVIDER: S-EPMC6363873 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature