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

Research output: Contribution to JournalArticleAcademicpeer-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 languageEnglish
Pages (from-to)1413-1425.e14
JournalCell
Volume173
Issue number6
DOIs
Publication statusPublished - 31 May 2018

Bibliographical note

Copyright © 2018 Elsevier Inc. All rights reserved.

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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