Overcoming intrinsic multi-drug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells

By A. Roesch, A. Vultur, I. Bogeski, Huang Wang, Katharina M Zimmermann, D. Speicher, C. Körbel, M. Laschke, P. Gimotty, S. Philipp and 9 more. Cancer Cell, 2013

625 citations recorded by the source corpus.

Summary 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 multi-drug 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 (OXPHOS) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1Bhigh subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anti-cancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

View Paper: https://www.semanticscholar.org/paper/8cb9f4515414a5b015279301679d451c9f0fbf16

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Citations in the corpus

Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “In lung cancer high KDM5A expression is associated with EGFR inhibitor resistance (Sharma et al., 2010), in melanoma quiescent cells required for tumor propagation that also play a role in resistance to chemotherapeutic agents and BRAF inhibitors have high KDM5B levels (Roesch et al., 2013).”
Metabolic reprogramming: the emerging concept and associated therapeutic strategies (2015, background): “Because histone H3 lysine 4 (H3K4)-demethylase JARID1B-highly expressing melanoma cells proliferate slowly and are highly dependent on mitochondrial metabolism [11, 40], chemotherapyinduced metabolic reprogramming in tumor tissue is likely to be responsible for the enrichment of CSCs in MRD.”
Epigenetic plasticity and the hallmarks of cancer (2017, background): “H3K4 demethylases (KDM5 family) enable lung and melanoma cell lines to evade antiproliferative therapies by adopting a slow-cycling persister state (64, 65).”
Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity (2020, background): “Roesch and colleagues identified another intrinsic resistance mechanism in BRAF V600E mediated malignant melanoma mediated by altered histone modifications [192].”
Toward Minimal Residual Disease-Directed Therapy in Melanoma. (2018, unknown): “Instead, drug tolerance is thought to be caused by the enrichment of a small subpopulation of cancer (stem) cells that is intrinsically refractory to the effects of anti-cancer drugs (Roesch et al., 2013; Trumpp and Wiestler, 2008).”