Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation

Shen, Shensi; Faouzi, Sara; Souquère, Sylvie; Roy, Séverine Le; Routier, Émilie; Libenciuc, C.; André, Fabrice; Pierron, Gérard; Scoazec, Jean‐Yves; Robert, Caroline

doi:10.1016/j.celrep.2020.108421

Cited by 82 publications

(65 citation statements)

References 84 publications

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“…The A375 cell line has BRAF V600E mutations, leading to excessive cellular proliferation and differentiation and increased cell survival. 11,27,37 BRAF is a protooncogene encoding a serine/threonine kinase of the RAF family. 38 GEM is a nucleoside that is an analog of deoxycytidine.…”

Section: Resultsmentioning

confidence: 99%

“…The team screened a diverse collection of compounds and found that two GPX4 inhibitors (RSL3 and ML210) were selectively lethal to persisters. In a separate study, Shen et al 27 revealed the existence of a metabolic mechanism, characterized by the upregulation of fatty acid oxidation, in the melanoma persister cell population mediated by BRAF and MEK inhibitors. Although many studies have shown that oxidative stress plays a critical role in persistence, 11,22,26,27 we first need to obtain a comprehensive understanding of the metabolic state of persister cells to explore their metabolism as a therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

“…In a separate study, Shen et al 27 revealed the existence of a metabolic mechanism, characterized by the upregulation of fatty acid oxidation, in the melanoma persister cell population mediated by BRAF and MEK inhibitors. Although many studies have shown that oxidative stress plays a critical role in persistence, 11,22,26,27 we first need to obtain a comprehensive understanding of the metabolic state of persister cells to explore their metabolism as a therapeutic target. We still need to elucidate (i) whether the metabolic rewiring observed in persister cells is a hallmark of cancer persistence, (ii) whether it is a transient state induced by cancer therapeutics and (iii) whether it depends on drug type, concentration and treatment duration.…”

Section: Introductionmentioning

confidence: 99%

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A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

Karki

Angardi

Mier

et al. 2021

Preprint

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Persister cells are defined as the small fraction of quiescent cells in a bulk cancer cell population that can tolerate unusually high levels of drugs. Persistence is a transient state that poses an important health concern in cancer therapy. The mechanisms associated with persister phenotypes are highly diverse and complex, and many aspects of persister cell physiology remain to be explored. We applied a melanoma cell line and panel of chemotherapeutic agents to show that melanoma persister cells are not necessarily preexisting dormant cells or stem cells; in fact, they may be induced by cancer chemotherapeutics. Our metabolomics analysis and phenotype microarray assays further demonstrated that the levels of Krebs cycle molecules are significantly lower in the melanoma persister subpopulation than in the untreated bulk cell population due to increased utilization rates in persisters. Our data indicate that this observed metabolic remodeling is transient, as the consumption rates of Krebs cycle metabolites are significantly reduced in the progenies of persisters. Given that the mitochondrial electron transport chain (ETC) is more active in the persister subpopulation than in the bulk cancer cell population, we also verified that targeting ETC activity can reduce melanoma persistence. The reported metabolic remodeling feature seems to be a conserved characteristic of melanoma persistence, as it has been observed in various melanoma persister subpopulations derived from a diverse range of chemotherapeutics. Elucidating a global metabolic mechanism that contributes to persister survival and reversible switching will ultimately foster the development of novel cancer therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

Karki

Angardi

Mier

et al. 2021

Preprint

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show abstract

“…To survive to the metabolic stress induced by MAPK inhibitors, tolerant BRAF-mutated melanoma must become dependent on oxidative respiration through the use of glutamine [ 67 ]. Recently, evidence indicated that tolerant BRAF-mutated cells also use lipids as additional nutrient sources to survive in the presence of MAPK inhibitors [ 30 ]. Thus, tolerant cells switch from glycolysis to complete FAO both in peroxisomes and mitochondria to adapt to metabolic stress induced by MAPK inhibitors.…”

Section: Changes In Lipid Metabolism Occur In Drug-tolerant Cancermentioning

confidence: 99%

“…FAO takes place in the mitochondrial matrix and consists in a cyclical catabolic reaction providing nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FADH2), NADPH and ATP. Interestingly, besides mitochondria, FAO was also observed in peroxisomes within cancer cells [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Lipid Metabolism and Resistance to Anticancer Treatment

Germain

Dhayer

Boileau

et al. 2020

Biology

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Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells’ sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance.

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Metabolic reprogramming in cancer: Mechanisms and therapeutics

Nong

Han

et al. 2023

MedComm

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Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor–host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.

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Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation

Cited by 82 publications

References 84 publications

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

Lipid Metabolism and Resistance to Anticancer Treatment

Metabolic reprogramming in cancer: Mechanisms and therapeutics

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