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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Small Molecule Therapeutics

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

Thao N.D. Pham, Krishan Kumar, Brian T. DeCant, Meng Shang, Samad Z. Munshi, Maria Matsangou, Kazumi Ebine and Hidayatullah G. Munshi
Thao N.D. Pham
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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  • For correspondence: h-munshi@northwestern.eduthao.pham@northwestern.edu
Krishan Kumar
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.
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Brian T. DeCant
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Meng Shang
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.Jesse Brown VA Medical Center, Chicago, Illinois.
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Samad Z. Munshi
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Maria Matsangou
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.
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Kazumi Ebine
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.Jesse Brown VA Medical Center, Chicago, Illinois.
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Hidayatullah G. Munshi
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.Jesse Brown VA Medical Center, Chicago, Illinois.
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  • For correspondence: h-munshi@northwestern.eduthao.pham@northwestern.edu
DOI: 10.1158/1535-7163.MCT-18-0768 Published February 2019
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received July 11, 2018.
  • Revision received October 10, 2018.
  • Accepted November 13, 2018.
  • Published first November 16, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (2)
February 2019
Volume 18, Issue 2
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Induction of MNK Kinase–dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors
Thao N.D. Pham, Krishan Kumar, Brian T. DeCant, Meng Shang, Samad Z. Munshi, Maria Matsangou, Kazumi Ebine and Hidayatullah G. Munshi
Mol Cancer Ther February 1 2019 (18) (2) 235-244; DOI: 10.1158/1535-7163.MCT-18-0768

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Induction of MNK Kinase–dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors
Thao N.D. Pham, Krishan Kumar, Brian T. DeCant, Meng Shang, Samad Z. Munshi, Maria Matsangou, Kazumi Ebine and Hidayatullah G. Munshi
Mol Cancer Ther February 1 2019 (18) (2) 235-244; DOI: 10.1158/1535-7163.MCT-18-0768
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Molecular Cancer Therapeutics
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