American Association for Cancer Research
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Supplementary Figures 1-3 from Induction of MNK Kinase–dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors

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posted on 2023-04-03, 15:45 authored by Thao N.D. Pham, Krishan Kumar, Brian T. DeCant, Meng Shang, Samad Z. Munshi, Maria Matsangou, Kazumi Ebine, Hidayatullah G. Munshi

Fig. S1 - eIF4E expression and survival data for papillary thyroid. Fig. S2 - Effect of BET inhibitors on genes regulating cytoskeleton Fig. S3 - combination of MNK inhibitors and OTX015 or ARV-825

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ARTICLE 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. Significantly, MNK inhibitors and MNK1/2 knockdown enhanced the efficacy of BETis in suppressing proliferation of cancer cells in vitro and in a syngeneic mouse model. Together, these results demonstrate a novel prosurvival feedback signaling induced by BETis, providing a mechanistic rationale for combination therapy with BET and MNK inhibitors for synergistic inhibition of cancer cells.

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    Molecular Cancer Therapeutics

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    Drug ResistanceNovel mechanismsReversal of drug resistance

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