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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| Format: | Article |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/7/1744 |
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| author | Jade Lyons Rimmer Emanuela Ercolano Daniele Baiz Mahindra Makhija Allison Berger Todd Sells Steve Stroud David Hilton Claire L. Adams C Oliver Hanemann |
| author_facet | Jade Lyons Rimmer Emanuela Ercolano Daniele Baiz Mahindra Makhija Allison Berger Todd Sells Steve Stroud David Hilton Claire L. Adams C Oliver Hanemann |
| author_sort | Jade Lyons Rimmer |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T18:47:20Z |
| format | Article |
| id | doaj.art-4bb45e00a41042db92d0bda5dec613db |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:47:20Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4bb45e00a41042db92d0bda5dec613db2023-11-20T05:25:55ZengMDPI AGCancers2072-66942020-06-01127174410.3390/cancers12071744The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient MeningiomaJade Lyons Rimmer0Emanuela Ercolano1Daniele Baiz2Mahindra Makhija3Allison Berger4Todd Sells5Steve Stroud6David Hilton7Claire L. Adams8C Oliver Hanemann9Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL68BU, UKPeninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL68BU, UKPeninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL68BU, UKTakeda International UK, 1 Kingdom Street, London W2 6BD, UKMillennium Pharmaceuticals, Inc. a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA 02139, USAMillennium Pharmaceuticals, Inc. a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA 02139, USAMillennium Pharmaceuticals, Inc. a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA 02139, USADepartment of Histopathology, University Hospitals Plymouth NHS Trust, Plymouth, Devon PL6 8DH, UKPeninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL68BU, UKPeninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL68BU, UKMeningioma 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.https://www.mdpi.com/2072-6694/12/7/1744MerlinmeningiomaCRL4-DCAF1KSR1Raf/MEK/ERK |
| spellingShingle | Jade Lyons Rimmer Emanuela Ercolano Daniele Baiz Mahindra Makhija Allison Berger Todd Sells Steve Stroud David Hilton Claire L. Adams C Oliver Hanemann The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma Cancers Merlin meningioma CRL4-DCAF1 KSR1 Raf/MEK/ERK |
| 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 | Merlin meningioma CRL4-DCAF1 KSR1 Raf/MEK/ERK |
| url | https://www.mdpi.com/2072-6694/12/7/1744 |
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