Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells
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Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.
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Collectively, these studies support a model wherein a pre-existing sub-population of drug-tolerant tumor cells is enriched upon drug treatment, akin to the principle of non-genetic Darwinian selection.
“Collectively, these studies support a model wherein a pre-existing sub-population of drug-tolerant tumor cells is enriched upon drug treatment, akin to the principle of non-genetic Darwinian selection [60,62,63].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [60]
Some studies indicate that drug-tolerant persister populations or cancer cells primed to persist exist even prior to treatment.
“Some studies indicate that drug-tolerant persister populations or cancer cells that are primed to persist exist even prior to treatment [40,43,60,61].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [60]
Melanoma cell lines treated with diverse anticancer drugs, such as cisplatin, bortezomib, and the BRAF inhibitor vemurafenib, were enriched for resistant JARID1Bhigh melanoma cells with increased expression of mitochondrial proteins involved in bioenergetic metabolism.
“Roesch and colleagues found that melanoma cell lines treated with diverse anticancer drugs, such as cisplatin, bortezomib, and the BRAF inhibitor vemurafenib, were enriched for resistant JARID1Bhigh melanoma cells with increased expression of mitochondrial proteins involved in bioenergetic metabolism [60].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [60]
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- Authors
- Roesch, A., Vultur, A., Bogeski, I., Wang, H., Zimmermann, K. M., Speicher, D., Körbel, C., Laschke, M. W., Gimotty, P. A., Philipp, S. E., Krause, E., Pätzold, S., Villanueva, J., Krepler, C., Fukunaga-Kalabis, M., Hoth, M., Bastian, B. C., Vogt, T., & Herlyn, M.
- Affiliations
- The Wistar Institute (US)
- Saarland University (DE)
- Universitätsklinikum des Saarlandes (DE)
- University of Pennsylvania (US)
- Goethe University Frankfurt (DE)
- University of California, San Francisco (US)
- Corresponding author
- Roesch, Alexander
- Herlyn, Meenhard
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 23
- Issue
- 6
- Pages
- 811-825
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3810180
- OpenAlex
- W1995103178
- Cited by
- 670
- References
- 33
- Citations by year
- 2026: 18 · 2025: 46 · 2024: 48 · 2023: 43 · 2022: 50 · 2021: 69 · 2020: 70 · 2019: 66 · 2018: 61 · 2017: 56 · 2016: 49 · 2015: 46 · 2014: 37 · 2013: 10
- FWCI
- 21.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA047159, CA-10815, CA-25874, CA047159, P01CA025874, P30CA010815, P30CA016520)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- melanoma, JARID1B, KDM5B, H3K4 demethylation, mitochondrial respiration, oxidative phosphorylation, vemurafenib, cisplatin, BRAF V600E inhibitors, tumor cell subpopulations, drug resistance
- MeSH terms
- Vemurafenib, Antineoplastic Agents, Cisplatin, Electron Transport, Humans, Indoles, Melanoma, Nuclear Proteins, Oligomycins, Repressor Proteins, Sulfonamides, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Jumonji Domain-Containing Histone Demethylases
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