TY - JOUR
T1 - An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential
AU - Wang, Liqin
AU - Leite de Oliveira, Rodrigo
AU - Huijberts, Sanne
AU - Bosdriesz, Evert
AU - Pencheva, Nora
AU - Brunen, Diede
AU - Bosma, Astrid
AU - Song, Ji-Ying
AU - Zevenhoven, John
AU - Los-de Vries, G Tjitske
AU - Horlings, Hugo
AU - Nuijen, Bastiaan
AU - Beijnen, Jos H
AU - Schellens, Jan H M
AU - Bernards, Rene
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018/5/31
Y1 - 2018/5/31
N2 - 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.
AB - 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.
KW - Amino Acid Transport System y+/metabolism
KW - Animals
KW - Apoptosis
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Drug Resistance, Neoplasm
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Humans
KW - MAP Kinase Kinase 1/metabolism
KW - MAP Kinase Signaling System
KW - Melanoma/drug therapy
KW - Mice
KW - Mutation
KW - Neoplasm Transplantation
KW - Protein Kinase Inhibitors/pharmacology
KW - Proto-Oncogene Proteins B-raf/genetics
KW - Reactive Oxygen Species/metabolism
KW - Skin Neoplasms/drug therapy
KW - Treatment Outcome
KW - Vorinostat/pharmacology
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U2 - 10.1016/j.cell.2018.04.012
DO - 10.1016/j.cell.2018.04.012
M3 - Article
C2 - 29754815
SN - 0092-8674
VL - 173
SP - 1413-1425.e14
JO - Cell
JF - Cell
IS - 6
ER -