An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential

Liqin Wang; Rodrigo Leite de Oliveira; Sanne Huijberts; Evert Bosdriesz; Nora Pencheva; Diede Brunen; Astrid Bosma; Ji-Ying Song; John Zevenhoven; G Tjitske Los-de Vries; Hugo Horlings; Bastiaan Nuijen; Jos H Beijnen; Jan H M Schellens; Rene Bernards

doi:10.1016/j.cell.2018.04.012

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential

Liqin Wang
, Rodrigo Leite de Oliveira
, Sanne Huijberts
, Evert Bosdriesz
, Nora Pencheva
, Diede Brunen
, Astrid Bosma
, Ji-Ying Song
, John Zevenhoven
, G Tjitske Los-de Vries
, Hugo Horlings
, Bastiaan Nuijen
, Jos H Beijnen
, Jan H M Schellens
, Rene Bernards

Oncode Institute
The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Cancer Systems Biology Center (CSBC), The Netherlands Cancer Institute, Amsterdam, the Netherlands. The NKI Robotics and Screening Center (NRSC), The Netherlands Cancer Institute, Amsterdam, the Netherlands. [email protected].

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1413-1425.e14
Journal	Cell
Volume	173
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2018.04.012
Publication status	Published - 31 May 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Amino Acid Transport System y+/metabolism
Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic/drug effects
Histone Deacetylase Inhibitors/pharmacology
Humans
MAP Kinase Kinase 1/metabolism
MAP Kinase Signaling System
Melanoma/drug therapy
Mice
Mutation
Neoplasm Transplantation
Protein Kinase Inhibitors/pharmacology
Proto-Oncogene Proteins B-raf/genetics
Reactive Oxygen Species/metabolism
Skin Neoplasms/drug therapy
Treatment Outcome
Vorinostat/pharmacology

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10.1016/j.cell.2018.04.012

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Wang, L., Leite de Oliveira, R., Huijberts, S., Bosdriesz, E., Pencheva, N., Brunen, D., Bosma, A., Song, J.-Y., Zevenhoven, J., Los-de Vries, G. T., Horlings, H., Nuijen, B., Beijnen, J. H., Schellens, J. H. M., & Bernards, R. (2018). An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential. Cell, 173(6), 1413-1425.e14. https://doi.org/10.1016/j.cell.2018.04.012

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title = "An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential",

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 = "Amino Acid Transport System y+/metabolism, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic/drug effects, Histone Deacetylase Inhibitors/pharmacology, Humans, MAP Kinase Kinase 1/metabolism, MAP Kinase Signaling System, Melanoma/drug therapy, Mice, Mutation, Neoplasm Transplantation, Protein Kinase Inhibitors/pharmacology, Proto-Oncogene Proteins B-raf/genetics, Reactive Oxygen Species/metabolism, Skin Neoplasms/drug therapy, Treatment Outcome, Vorinostat/pharmacology",

author = "Liqin Wang and \{Leite de Oliveira\}, Rodrigo and Sanne Huijberts and Evert Bosdriesz and Nora Pencheva and Diede Brunen and Astrid Bosma and Ji-Ying Song and John Zevenhoven and \{Los-de Vries\}, \{G Tjitske\} and Hugo Horlings and Bastiaan Nuijen and Beijnen, \{Jos H\} and Schellens, \{Jan H M\} and Rene Bernards",

year = "2018",

month = may,

day = "31",

doi = "10.1016/j.cell.2018.04.012",

language = "English",

volume = "173",

pages = "1413--1425.e14",

journal = "Cell",

issn = "0092-8674",

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}

Wang, L, Leite de Oliveira, R, Huijberts, S, Bosdriesz, E, Pencheva, N, Brunen, D, Bosma, A, Song, J-Y, Zevenhoven, J, Los-de Vries, GT, Horlings, H, Nuijen, B, Beijnen, JH, Schellens, JHM & Bernards, R 2018, 'An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential', Cell, vol. 173, no. 6, pp. 1413-1425.e14. https://doi.org/10.1016/j.cell.2018.04.012

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

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

U2 - 10.1016/j.cell.2018.04.012

DO - 10.1016/j.cell.2018.04.012

M3 - Article

SN - 0092-8674

VL - 173

SP - 1413-1425.e14

JO - Cell

JF - Cell

IS - 6

ER -

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential

Abstract

UN SDGs

Keywords

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