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Metabolic targeting as a strategy to overcome targeted therapy resistance in NRAS-mutated melanoma

ABSTRACT: We used single cell RNA sequencing (scRNA-seq) to analyze the molecular response of melanoma xenografts to combined MEK-inhibitng and metabolic targeting therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222258 | GEO | 2024/01/10

REPOSITORIES: GEO

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Targeted radionuclide therapy for pigmented BRAF- and NRAS-mutated melanoma: [131I]ICF01012 efficacy and combination with MAPK/ERK pathway inhibitors

Project description:Purpose: Tumor radioresistance can be driven by ERK phosphorylation and its downstream targets. In this context, melanomas harboring constitutive MAPK/ERK activation have been considered for targeted radionuclide therapy (TRT) with a radiolabeled melanin tracer ([131I]ICF01012), alone or in combination with MEK inhibitors (MEKi). Experimental design: We used three dimensional (3D) melanoma spheroid models to evaluate the effects of TRT in combination with MEKi, in human BRAFV600E SK-MEL-3, NRASQ61K 1007 and WT B16F10 murine melanomas. TRT was assessed in vivo using the syngeneic model C57Bl5/NRAS 1007 for biodistribution, dosimetry, efficiency and molecular mechanisms. Results: In spheroids, TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant models that were resistant to TRT-induced apoptosis. However NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. Actually, mice bearing NRAS1007 melanoma and receiving 18.5MBq of [131I]ICF01012 had a significant extended survival (median: 92 vs 44 days, p < 0.0001), associated with a 93 Gy tumor deposit, leading to a dramatic decrease of tumor growth. Furthermore, the number of lymph node metastases was reduced in mice receiving [131I]ICF01012. Comparative transcriptomic analyses confirm a decrease of mitosis, proliferation and metastasis signature in TRT-treated tumors vs control tumors. These analyses also suggest that in this NRAS-melanoma, TRT acts through an increase of oxidation and inflammation as well as P53 activation. Conclusions: Our data support the view that combining [131I]ICF01012-TRT with MEKi can be of benefit for the treatment of advanced pigmented BRAF-mutant melanoma. Likewise, [131I]ICF01012 alone can be considered as a new potential NRAS-mutant melanoma treatment.

2021-03-31 | GSE162536 | GEO

Melanoma NRAS - Cooperative induction of apoptosis in nras mutant melanoma by inhibition of mek and rock

Project description:In the present work we propose a new therapy for NRAS mutant melanoma. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma.

2015-03-11 | PXD000528 | Pride

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

Project description:BRAF V600 mutation influences cellular signaling pathways for melanoma development. Here, we show that mutated BRAF plays an essential role in the adaptive stress response following activation of general control non-derepressible 2 (GCN2) kinase. In parallel with GCN2, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators during nutrient stress and BRAF-targeted, therapeutic stress. Upon pharmacological BRAF inhibition, this signaling pathway exhibits temporal resistance, compared with the MEK-ERK pathway, thereby enabling transient induction of ATF4 under GCN2 activation. Notably, the prevention of GCN2 activation, using a chemical inhibitor that we identified, produces synergistic cell killing with BRAF inhibition. Thus, oncogenic BRAF can collaborate with the GCN2–ATF4 pathway, promoting stress adaptation for cell survival.

2020-04-06 | GSE136614 | GEO

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

2020-04-06 | GSE136613 | GEO

Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance: elevated P2RX7 levels indicate response to targeted therapy

Project description:While effective therapy is available for melanoma patients harbouring BRAF mutations, to date, the efficient therapeutic approaches for NRAS-mutant melanoma patients are limited. Therapeutic regimen involving combinatorial inhibition of MEK1/2 and CDK4/6 prove to be beneficial as targeted therapy for NRAS-mutant melanoma. Yet, only a subset of melanoma patients responded to this treatment, whereas acquired resistance eventually emerge in responders. Upon prolonged therapy with MEK1/2 and CDK4/6 inhibitors cells switch to fully drug-resistant or senescent phenotype in vitro. Consequently, there is a necessity to portray cell populations sensitive to targeted therapy, but also cell transitions associated with NRAS-mutant melanoma resistance. To define transcriptional states arising under indicated therapy and cell fate decisions governing resistance, we performed single-cell RNA sequencing at four distinguished time points during treatment. In this study, we identified a cell population highly enriched in calcium signalling, among others, associated with positive drug response. In particular, prolonged expression of ATP-gated ion channel P2RX7 was related to a senescent-like phenotype. Next, we described an immune-like melanoma state that acquired drug resistance and re-enter the cell cycle under treatment, as well as cell populations with intrinsic potential to evade drug pressure.

2023-04-26 | GSE230538 | GEO

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Project description: Not available

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Targeting mutant NRAS signaling pathways in melanoma.

Project description: Not available

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Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma.

Project description: Not available

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Reprogramming of bivalent chromatin states in NRAS-mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

Project description:The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers and therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS-mutants with bivalent H3K27me3 and Polycomb Repressive Complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1 and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS-mutants. Coincident with bivalent reprogramming the increased expression of pro-metastatic and melanocyte-specific cell identity genes are associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma, and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS-mutant melanoma patients.

2019-11-07 | GSE134043 | GEO

HSP70 inhibition synergizes with MEK inhibition for the treatment of NRAS mutant melanoma

Project description:NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against NRAS, along with acquired and adaptive resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for this tumor type. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma, and at the same time investigated the impact of the brain micro-environment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. This led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, but this is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEK inhibitors, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEK inhibitors against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma.

2022-06-30 | GSE179235 | GEO

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