An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential
Copyright © 2018 Elsevier Inc. All rights reserved..
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
| Errataetall: |
CommentIn: Nat Rev Cancer. 2018 Jul;18(7):403. - PMID 29872113 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:173 |
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| Enthalten in: |
Cell - 173(2018), 6 vom: 31. Mai, Seite 1413-1425.e14 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Liqin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.03.2019 Date Revised 03.01.2021 published: Print-Electronic CommentIn: Nat Rev Cancer. 2018 Jul;18(7):403. - PMID 29872113 Citation Status MEDLINE |
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| doi: |
10.1016/j.cell.2018.04.012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM284015156 |
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| 500 | |a CommentIn: Nat Rev Cancer. 2018 Jul;18(7):403. - PMID 29872113 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2018 Elsevier Inc. All rights reserved. | ||
| 520 | |a BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here | ||
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| 700 | 1 | |a Huijberts, Sanne |e verfasserin |4 aut | |
| 700 | 1 | |a Bosdriesz, Evert |e verfasserin |4 aut | |
| 700 | 1 | |a Pencheva, Nora |e verfasserin |4 aut | |
| 700 | 1 | |a Brunen, Diede |e verfasserin |4 aut | |
| 700 | 1 | |a Bosma, Astrid |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Ji-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Zevenhoven, John |e verfasserin |4 aut | |
| 700 | 1 | |a Los-de Vries, G Tjitske |e verfasserin |4 aut | |
| 700 | 1 | |a Horlings, Hugo |e verfasserin |4 aut | |
| 700 | 1 | |a Nuijen, Bastiaan |e verfasserin |4 aut | |
| 700 | 1 | |a Beijnen, Jos H |e verfasserin |4 aut | |
| 700 | 1 | |a Schellens, Jan H M |e verfasserin |4 aut | |
| 700 | 1 | |a Bernards, Rene |e verfasserin |4 aut | |
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