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Cell. 2018 May 31;173(6):1413-1425.e14. doi: 10.1016/j.cell.2018.04.012. Epub 2018 May 10.

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.

Author information

1
Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
2
Division of Clinical Pharmacology, Oncode Institute, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
3
Division of Molecular Genetics, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
4
Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
5
Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.

Abstract

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.

KEYWORDS:

HDAC inhibitors; drug resistance; melanoma; reactive oxygen species

PMID:
29754815
DOI:
10.1016/j.cell.2018.04.012

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