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Ferris J, Espona-Fiedler M, Hamilton C, et al. Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer. Cell Death Discov. 2020;6:61doi: 10.1038/s41420-020-00296-w.
Ferris, J., Espona-Fiedler, M., Hamilton, C., Holohan, C., Crawford, N., McIntyre, A. J., Roberts, J. Z., Wappett, M., McDade, S. S., Longley, D. B., & Coyle, V. (2020). Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer. Cell death discovery, 661. https://doi.org/10.1038/s41420-020-00296-w
Ferris, Jennifer, et al. "Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer." Cell death discovery vol. 6 (2020): 61. doi: https://doi.org/10.1038/s41420-020-00296-w
Ferris J, Espona-Fiedler M, Hamilton C, Holohan C, Crawford N, McIntyre AJ, Roberts JZ, Wappett M, McDade SS, Longley DB, Coyle V. Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer. Cell Death Discov. 2020 Jul 21;6:61. doi: 10.1038/s41420-020-00296-w. eCollection 2020. PMID: 32714568; PMCID: PMC7374701.
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Cell Death Discov. 2020 Jul 21;6:61. doi: 10.1038/s41420-020-00296-w. eCollection 2020.

Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer.

Cell death discovery

Jennifer Ferris, Margarita Espona-Fiedler, Claudia Hamilton, Caitriona Holohan, Nyree Crawford, Alex J McIntyre, Jamie Z Roberts, Mark Wappett, Simon S McDade, Daniel B Longley, Victoria Coyle

Affiliations

  1. Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL UK.

PMID: 32714568 PMCID: PMC7374701 DOI: 10.1038/s41420-020-00296-w

Abstract

Pevonedistat (MLN4924), a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit (NAE1), has demonstrated significant therapeutic potential in several malignancies. Although multiple mechanisms-of-action have been identified, how MLN4924 induces cell death and its potential as a combinatorial agent with standard-of-care (SoC) chemotherapy in colorectal cancer (CRC) remains largely undefined. In an effort to understand MLN4924-induced cell death in CRC, we identified p53 as an important mediator of the apoptotic response to MLN4924. We also identified roles for the extrinsic (TRAIL-R2/caspase-8) and intrinsic (BAX/BAK) apoptotic pathways in mediating the apoptotic effects of MLN4924 in CRC cells, as well as a role for BID, which modulates a cross-talk between these pathways. Depletion of the anti-apoptotic protein FLIP, which we identify as a novel mediator of resistance to MLN4924, enhanced apoptosis in a p53-, TRAIL-R2/DR5-, and caspase-8-dependent manner. Notably, TRAIL-R2 was involved in potentiating the apoptotic response to MLN4924 in the absence of FLIP, in a ligand-independent manner. Moreoever, when paired with SoC chemotherapies, MLN4924 demonstrated synergy with the irinotecan metabolite SN38. The cell death induced by MLN4924/SN38 combination was dependent on activation of mitochondria through BAX/BAK, but in a p53-independent manner, an important observation given the high frequency of

© The Author(s) 2020.

Keywords: Colon cancer

Conflict of interest statement

Conflict of interestThe authors declare that they have no conflict of interest.

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