Genetic Layout of Melanoma Lesions Is Associated with BRAF/MEK-Targeted Therapy Resistance and Transcriptional Profiles

Vergani, Elisabetta; Busico, Adele; Dugo, Matteo; Devecchi, Andrea; Valeri, Barbara; Cossa, Mara; Guardo, Lorenza Di; Cecco, Loris De; Feltrin, Erika; Valle, Giorgio; Deho, Paola; Frigerio, Simona; Lalli, Luca; Gallino, G.; Vecchio, Michele Del; Santinami, Mario; Pruneri, Giancarlo; Tamborini, Elena; Rivoltini, Licia; Sensi, Marialuisa; Vallacchi, Viviana; Rodolfo, Monica

doi:10.1016/j.jid.2022.04.027

Cited by 8 publications

(10 citation statements)

References 47 publications

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“…Given that lipid metabolic reprogramming appeared to be associated with the BRAFi-resistant phenotype, we examined if it was also accompanied by an alteration of lipid composition in the resistant cell lines. In a first set of experiments, we evaluated the total FA profile of three matched resistant and sensitive cell lines, selected based on their marked BRAFi-resistant phenotype ( Vergani et al, 2022 ). Experiments were performed after 24 h cell culture in the absence of serum, in order to avoid possible confounding effects by FBS lipids.…”

Section: Resultsmentioning

confidence: 99%

“…Conversely, no variation in GPX4 expression is found following lipid deprivation in LM16 and LM16R cells. This could be dependent on the different molecular background of the two cell line pairs ( Vergani et al, 2022 ). As far as ferroptosis is concerned, we hypothesized that cellular mechanisms not related to MDA levels are implicated.…”

Section: Discussionmentioning

confidence: 99%

“…The melanoma cell lines LM16, LM36, LM47, and the corresponding PLX4032-resistant sublines LM16R, LM36R and LM47R generated upon chronic exposure of parental cells to PLX4032, were derived at the Fondazione IRCCS, Istituto Nazionale dei Tumori of Milan ( Daniotti et al, 2004 ; Vergani et al, 2011 ; Vergani et al, 2022 ). All cell lines were cultured in RPMI-1640 medium (Lonza, Basel, Switzerland), supplemented with 10% FBS (Euroclone, Milan, Italy), used within 20 passages from thawing from a frozen stock, tested to verify the maintenance of resistance, routinely checked for mycoplasma contamination (Mycoalert, Lonza), and authenticated using the Stem Elite ID System (Promega, Wisconsin, United States).…”

Section: Methodsmentioning

confidence: 99%

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Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma

Vergani

Beretta

Aloisi

et al. 2022

Front. Cell Dev. Biol.

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Drug resistance limits the achievement of persistent cures for the treatment of melanoma, in spite of the efficacy of the available drugs. The aim of the present study was to explore the involvement of lipid metabolism in melanoma resistance and assess the effects of its targeting in cellular models of melanoma with acquired resistance to the BRAF-inhibitor PLX4032/Vemurafenib. Since transcriptional profiles pointed to decreased cholesterol and fatty acids synthesis in resistant cells as compared to their parental counterparts, we examined lipid composition profiles of resistant cells, studied cell growth dependence on extracellular lipids, assessed the modulation of enzymes controlling the main nodes in lipid biosynthesis, and evaluated the effects of targeting Acetyl-CoA Acetyltransferase 2 (ACAT2), the first enzyme in the cholesterol synthesis pathway, and Acyl-CoA Cholesterol Acyl Transferase (ACAT/SOAT), which catalyzes the intracellular esterification of cholesterol and the formation of cholesteryl esters. We found a different lipid composition in the resistant cells, which displayed reduced saturated fatty acids (SFA), increased monounsaturated (MUFA) and polyunsaturated (PUFA), and reduced cholesteryl esters (CE) and triglycerides (TG), along with modulated expression of enzymes regulating biosynthetic nodes of the lipid metabolism. The effect of tackling lipid metabolism pathways in resistant cells was evidenced by lipid starvation, which reduced cell growth, increased sensitivity to the BRAF-inhibitor PLX4032, and induced the expression of enzymes involved in fatty acid and cholesterol metabolism. Molecular targeting of ACAT2 or pharmacological inhibition of SOAT by avasimibe showed antiproliferative effects in melanoma cell lines and a synergistic drug interaction with PLX4032, an effect associated to increased ferroptosis. Overall, our findings reveal that lipid metabolism affects melanoma sensitivity to BRAF inhibitors and that extracellular lipid availability may influence tumor cell response to treatment, a relevant finding in the frame of personalized therapy. In addition, our results indicate new candidate targets for drug combination treatments.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma

Vergani

Beretta

Aloisi

et al. 2022

Front. Cell Dev. Biol.

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“…Melanoma cells were shown to be able to take up lipids from extracellular vesicles released by stromal adipocytes or from aged fibroblasts by fatty acid transport protein (FATP) and use those to survive upon targeted therapy [19][20][21]. Dysregulation of CHOL homeostasis in melanoma cells was shown to impact proliferation, migration, and invasion, and overexpression of CHOL synthesis genes was associated with poor disease prognosis and drug resistance [10,22]. High prostaglandin E2 (PGE2) synthesis and increased FA oxidation are associated with poor prognosis in melanoma patients after targeted therapy with BRAFi/MEKi [6,21,23].…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that transcriptomes of BRAFi/MEKi-resistant melanoma are characterized by dysregulated lipid metabolism pathways involving FA and CHOL [10] and determining alterations in the lipid composition, particularly in different classes of FA, cholesteryl esters (CE) and triglycerides (TG), along with modulated expression of enzymes regulating biosynthetic nodes of the lipid metabolism [11]. The effect of tackling lipid metabolism pathways in resistant cell lines was evidenced by lipid starvation, which reduced cell growth and increased sensitivity to the BRAFi PLX4032/vemurafenib [11].…”

Section: Introductionmentioning

confidence: 99%

Alterations in Plasma Lipid Profiles Associated with Melanoma and Therapy Resistance

Dei Cas,

Ciniselli,

Vergani

et al. 2024

IJMS

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Dysfunctions of lipid metabolism are associated with tumor progression and treatment resistance of cutaneous melanoma. BRAF/MEK inhibitor resistance is linked to alterations of melanoma lipid pathways. We evaluated whether a specific lipid pattern characterizes plasma from melanoma patients and their response to therapy. Plasma samples from patients and controls were analyzed for FASN and DHCR24 levels and lipidomic profiles. FASN and DHCR24 expression resulted in association with disease condition and related to plasma cholesterol and triglycerides in patients at different disease stages (n = 144) as compared to controls (n = 115). Untargeted lipidomics in plasma (n = 40) from advanced disease patients and controls revealed altered levels of different lipids, including fatty acid derivatives and sphingolipids. Targeted lipidomics identified higher levels of dihydroceramides, ceramides, sphingomyelins, ganglioside GM3, sphingosine, sphingosine-1-phosphate, and dihydrosphingosine, saturated and unsaturated fatty acids. When melanoma patients were stratified based on a long/short-term clinical response to kinase inhibitors, differences in plasma levels were shown for saturated fatty acids (FA 16:0, FA18:0) and oleic acid (FA18:1). Our results associated altered levels of selected lipid species in plasma of melanoma patients with a more favorable prognosis. Although obtained in a small cohort, these results pave the way to lipidomic profiling for melanoma patient stratification.

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Determinants of resistance and response to melanoma therapy

Robertson,

Fane,

Weeraratna

et al. 2024

Nat Cancer

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Genetic Layout of Melanoma Lesions Is Associated with BRAF/MEK-Targeted Therapy Resistance and Transcriptional Profiles

Cited by 8 publications

References 47 publications

Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma

Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma

Alterations in Plasma Lipid Profiles Associated with Melanoma and Therapy Resistance

Determinants of resistance and response to melanoma therapy

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