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The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma

Meningioma is the most common primary intracranial tumour, and surgical resection is the main therapeutic option. Merlin is a tumour suppressor protein that is frequently mutated in meningioma. The activity of the E3 ubiquitin ligase complex, CRL4-DCAF1, and the Raf/MEK/ERK scaffold protein Kinase s...

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Autores principales: Lyons Rimmer, Jade, Ercolano, Emanuela, Baiz, Daniele, Makhija, Mahindra, Berger, Allison, Sells, Todd, Stroud, Steve, Hilton, David, Adams, Claire L., Hanemann, C Oliver
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407567/
https://www.ncbi.nlm.nih.gov/pubmed/32629964
http://dx.doi.org/10.3390/cancers12071744
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author Lyons Rimmer, Jade
Ercolano, Emanuela
Baiz, Daniele
Makhija, Mahindra
Berger, Allison
Sells, Todd
Stroud, Steve
Hilton, David
Adams, Claire L.
Hanemann, C Oliver
author_facet Lyons Rimmer, Jade
Ercolano, Emanuela
Baiz, Daniele
Makhija, Mahindra
Berger, Allison
Sells, Todd
Stroud, Steve
Hilton, David
Adams, Claire L.
Hanemann, C Oliver
author_sort Lyons Rimmer, Jade
collection PubMed
description Meningioma is the most common primary intracranial tumour, and surgical resection is the main therapeutic option. Merlin is a tumour suppressor protein that is frequently mutated in meningioma. The activity of the E3 ubiquitin ligase complex, CRL4-DCAF1, and the Raf/MEK/ERK scaffold protein Kinase suppressor of Ras 1 (KSR1) are upregulated in Merlin-deficient tumours, which drives tumour growth. Identifying small molecules that inhibit these key pathways may provide an effective treatment option for patients with meningioma. We used meningioma tissue and primary cells derived from meningioma tumours to investigate the expression of DDB1 and Cullin 4-associated factor 1 (DCAF1) and KSR1, and confirmed these proteins were overexpressed. We then used primary cells to assess the therapeutic potential of MLN3651, a neddylation inhibitor which impacts the activity of the CRL family of E3 ubiquitin ligases and the MAPK/ERK kinase (MEK1/2) inhibitor selumetinib. MLN3651 treatment reduced proliferation and activated apoptosis, whilst increasing Raf/MEK/ERK pathway activation. The combination of MLN3651 and the MEK1/2 inhibitor selumetinib prevented the increase in Raf/MEK/ERK activity, and had an additive effect compared with either treatment alone. Therefore, the combined targeting of CRL4-DCAF1 and Raf/MEK/ERK activity represents an attractive novel strategy in the treatment of Merlin-deficient meningioma.
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spelling pubmed-74075672020-08-25 The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma Lyons Rimmer, Jade Ercolano, Emanuela Baiz, Daniele Makhija, Mahindra Berger, Allison Sells, Todd Stroud, Steve Hilton, David Adams, Claire L. Hanemann, C Oliver Cancers (Basel) Article Meningioma is the most common primary intracranial tumour, and surgical resection is the main therapeutic option. Merlin is a tumour suppressor protein that is frequently mutated in meningioma. The activity of the E3 ubiquitin ligase complex, CRL4-DCAF1, and the Raf/MEK/ERK scaffold protein Kinase suppressor of Ras 1 (KSR1) are upregulated in Merlin-deficient tumours, which drives tumour growth. Identifying small molecules that inhibit these key pathways may provide an effective treatment option for patients with meningioma. We used meningioma tissue and primary cells derived from meningioma tumours to investigate the expression of DDB1 and Cullin 4-associated factor 1 (DCAF1) and KSR1, and confirmed these proteins were overexpressed. We then used primary cells to assess the therapeutic potential of MLN3651, a neddylation inhibitor which impacts the activity of the CRL family of E3 ubiquitin ligases and the MAPK/ERK kinase (MEK1/2) inhibitor selumetinib. MLN3651 treatment reduced proliferation and activated apoptosis, whilst increasing Raf/MEK/ERK pathway activation. The combination of MLN3651 and the MEK1/2 inhibitor selumetinib prevented the increase in Raf/MEK/ERK activity, and had an additive effect compared with either treatment alone. Therefore, the combined targeting of CRL4-DCAF1 and Raf/MEK/ERK activity represents an attractive novel strategy in the treatment of Merlin-deficient meningioma. MDPI 2020-06-30 /pmc/articles/PMC7407567/ /pubmed/32629964 http://dx.doi.org/10.3390/cancers12071744 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lyons Rimmer, Jade
Ercolano, Emanuela
Baiz, Daniele
Makhija, Mahindra
Berger, Allison
Sells, Todd
Stroud, Steve
Hilton, David
Adams, Claire L.
Hanemann, C Oliver
The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma
title The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma
title_full The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma
title_fullStr The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma
title_full_unstemmed The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma
title_short The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma
title_sort potential of mln3651 in combination with selumetinib as a treatment for merlin-deficient meningioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407567/
https://www.ncbi.nlm.nih.gov/pubmed/32629964
http://dx.doi.org/10.3390/cancers12071744
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