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Cited by 938Ferroptosis and cancer prognosisMelanoma and MAPK PathwaysCancer Immunotherapy and Biomarkers

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

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Tsoi, Jennifer, Robert, Lidia, Paraiso, Kim, Galvan, Carlos, Sheu, Katherine M., Lay, Johnson, Wong, Deborah J.L., Atefi, Mohammad +7 more·2018·Cancer Cell
DOI 10.1016/j.ccell.2018.03.017PMC PMC5953834
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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.

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  • In melanoma, ferroptosis-inducing agents such as IKE or RSL3 combined with vemurafenib reduced colony formation of invasive melanoma cells in vitro, possibly because of their lower levels of glutathione.

    “In melanoma, ferroptosis-inducing agents, such as the system Xc− inhibitor imidazole ketone erastin (IKE) or (1S, 3R)-RSL3 (RSL3) combined with the BRAF kinase inhibitor vemurafenib, reduced colony formation of invasive melanoma cells in vitro, possibly because of their lower levels of glutathione (10).”

    From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [10]

    The Results section on combination treatment (page unavailable) reports that erastin or RSL3 with vemurafenib substantially reduced long-term persisting melanoma cells in vitro. A separate Results section (page unavailable) links greater ferroptosis sensitivity in dedifferentiated cells to lower glutathione levels. The paper reports erastin, not IKE, and describes a reduction in persisting cells rather than specifically measuring colony formation of invasive cells. (LLM, conf=0.87)

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Authors
Tsoi, J., Robert, L., Paraiso, K., Galvan, C., Sheu, K. M., Lay, J., Wong, D. J. L., Atefi, M., Shirazi, R., Wang, X., Braas, D., Grasso, C. S., Palaskas, N., Ribas, A., & Graeber, T. G.
Affiliations
  • University of California, Los Angeles (US)
  • California NanoSystems Institute (US)
Corresponding author
Graeber, Thomas G.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2018-05
Volume
33
Issue
5
Pages
890-904.e5
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2018.03.017
PMC
PMC5953834
OpenAlex
W2797906965
Cited by
938
References
6
Citations by year
2026: 105 · 2025: 124 · 2024: 142 · 2023: 131 · 2022: 152 · 2021: 107 · 2020: 96 · 2019: 63 · 2018: 15 · 2012: 2
FWCI
52.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • William Caspar Graustein Memorial Fund
  • Jonsson Cancer Center Foundation
  • University of California, Los Angeles
  • American Cancer Society (RSG-12-257-01-TBE, 20120279)
  • Sociedad Española de Oncología Médica
  • National Center for Advancing Translational Sciences (UL1TR000124)
  • Conquer Cancer Foundation
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
melanoma, melanoma subtypes, differentiation trajectories, ferroptosis, receptor tyrosine kinase, immunotherapy, inflammatory signaling, melanoma cell lines, gene expression
MeSH terms
Vemurafenib, Cell Survival, Humans, Iron, Melanoma, Piperazines, Signal Transduction, Gene Expression Regulation, Neoplastic, Oxidative Stress, Drug Resistance, Neoplasm, DNA Methylation, Gene Expression Profiling, Cell Line, Tumor, Gene Regulatory Networks, Cell Dedifferentiation

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