An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Melanoma / genetics
  • Mice
  • Mutation
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Reactive Oxygen Species / metabolism
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Treatment Outcome
  • Vorinostat / pharmacology

Substances

  • Amino Acid Transport System y+
  • Histone Deacetylase Inhibitors
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • SLC7A11 protein, human
  • Vorinostat
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 1