Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

Jennifer Tsoi; Lidia Robert; Kim Paraiso; Carlos Galvan; Katherine M Sheu; Johnson Lay; Deborah J L Wong; Mohammad Atefi; Roksana Shirazi; Xiaoyan Wang; Daniel Braas; Catherine S Grasso; Nicolaos Palaskas; Antoni Ribas; Thomas G Graeber

doi:10.1016/j.ccell.2018.03.017

Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

Cancer Cell. 2018 May 14;33(5):890-904.e5. doi: 10.1016/j.ccell.2018.03.017. Epub 2018 Apr 12.

Authors

Affiliations

¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 570 Westwood Plaza, Building 114, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
² Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 570 Westwood Plaza, Building 114, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA.
⁴ Department of Medicine Statistics Core, UCLA, Los Angeles, CA 90095, USA.
⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 570 Westwood Plaza, Building 114, Los Angeles, CA 90095, USA; Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Department of Surgery, Division of Surgical-Oncology, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 570 Westwood Plaza, Building 114, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA. Electronic address: tgraeber@mednet.ucla.edu.

Abstract

Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.

Keywords: combination therapy; differentiation; ferroptosis; immunotherapy; kinase inhibitor therapy; melanoma; pharmacogenomics; systems biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Dedifferentiation
Cell Line, Tumor
Cell Survival / drug effects
DNA Methylation
Drug Resistance, Neoplasm / drug effects
Gene Expression Profiling / methods*
Gene Expression Regulation, Neoplastic / drug effects
Gene Regulatory Networks
Humans
Iron / metabolism*
Iron / toxicity
Melanoma / classification*
Melanoma / drug therapy
Melanoma / genetics*
Melanoma / metabolism
Oxidative Stress / drug effects
Piperazines
Signal Transduction
Vemurafenib / pharmacology*

Substances

Piperazines
erastin
Vemurafenib
Iron

Abstract

Publication types

MeSH terms

Substances

Grants and funding