EIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations
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PROVIDER: PRJNA1142920 | ENA |
REPOSITORIES: ENA
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Project description:The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel function of eIF4F in the negative regulation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for maintaining optimal ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
2024-10-04 | GSE273721 | GEO
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
Project description:NRAS and BRAF are the most commonly found genetic alterations in melanoma. It has been demonstrated that NRAS and BRAF oncogenic alterations, even affecting the same signaling pathway, represent two different clinical and biochemical entities, showing different signaling patterns and biological responses. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknown how the NRAS oncogene contributes to this cancer hallmark. We have showed that NRAS-mutated melanomas harbor specific metabolic alterations that render cells sensitive to RAS pathway inhibition upon metabolic stress. Gene expression analysis has confirmed different transcriptional profiles of NRAS- and BRAF- mutant cells both, under basal conditions and in response to glucose starvation. Moreover, analysis of glucose metabolism-related genes expression regulation revealed PFKFB2 as an important player linking glycolysis and RAS pathway activation.
2022-08-31 | E-MTAB-10921 | biostudies-arrayexpress
Project description:NRAS-mutated melanoma lacks an approved first-line treatment. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknow how the NRAS oncogene contributes to this cancer hallmark. Here, we show that NRASQ61-mutated melanomas harbor specific metabolic alterations that render cells sensitive to sorafenib upon metabolic stress. Mechanistically, these cells seem to depend on glucose metabolism, as glucose deprivation promotes the switch of the RAF isoform used from CRAF to BRAF. This process contributes to cell survival and sustains glucose metabolism through the phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/6- phosphofructo-2-kinase/fructose-2,6-bisphosph 3 (PFKFB2/PFKFB3) heterodimers by BRAF. In turn, this phosphorylation favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop linking glycolysis and the RAS signaling pathway. In vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with the combination of 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence of the contributions of NRAS oncogenes to metabolic rewiring and proof of principle for the treatment of NRAS-mutated melanoma with combinations of metabolic stress (glycolysis inhibitors) and already approved drugs such as sorafenib.
2023-01-09 | PXD028297 | Pride
Project description:One third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within six months. Treatment options for these patients remain limited. Here we analyse twenty BRAFV600 mutant melanoma metastases derived from 10 patients treated with the combination of debrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumors and MAPK reactivation occurred in 9/10 tumors, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein confers resistance to combination therapy, highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (e.g. RCA1 and AKT3) that activate the MAPK and P13K pathways and are thus predicted to diminish response to MAPK inhibitors. Total RNA obtained from fresh frozen melanoma tumors treated with a combination of dabrafenib and trametinib
2014-12-03 | E-GEOD-61992 | biostudies-arrayexpress
Project description:Malignant melanoma is characterized by frequent metastasis, however specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating beta-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and BrafV600E mutation, we demonstrate that beta-catenin is a central mediator of melanoma metastasis to lymph node and lung. In addition to altering metastasis, beta-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with beta-catenin stabilization are very similar to a subset of human melanomas; together these findings establish Wnt signaling as a metastasis regulator in melanoma. MoGene-1_0-st-v1: Four samples total. Two biological replicates of uncultured Pten/Braf murine melanomas and two biological replicates of uncultured Pten/Braf/Bcat-STA murine melanomas. MoEx-1_0-st-v1: Two samples total. Dissociated tumor and FACS-enriched Pten/Braf and Pten/Braf/Bcat-STA murine melanoma.
2011-10-12 | E-GEOD-32907 | biostudies-arrayexpress
Project description:One third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within six months. Treatment options for these patients remain limited. Here we analyse twenty BRAFV600 mutant melanoma metastases derived from 10 patients treated with the combination of debrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumors and MAPK reactivation occurred in 9/10 tumors, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein confers resistance to combination therapy, highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (e.g. RCA1 and AKT3) that activate the MAPK and P13K pathways and are thus predicted to diminish response to MAPK inhibitors.
2014-12-03 | GSE61992 | GEO
Project description:Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of plasma cells (PCs) in the bone marrow (BM). The genetic background and clinical course of the disease are largely heterogeneous, and MM pathophysiology ranges from the premalignant condition of monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM, symptomatic MM, and extramedullary MM/plasma cell leukemia (PCL). Recent genome-wide sequencing efforts have provided the rationale for molecularly aimed treatment approaches, identifying mutations that can be specifically targeted, such as those in the mitogen-activated protein kinase (MAPK) pathway, which represent the most prevalent mutations in MM. Among these, mutations affecting BRAF gene, detected in 4-15% of patients, are of potential immediate clinical relevance due to the availability of effective inhibitors of this serine-threonine kinase which are in fact being explored also in myeloma. In this study, we screened by next generation sequencing (NGS) a large and representative series of intramedullary and extramedullary MM patients, including primary and secondary plasma cell leukemia (pPCL and sPCL, respectively), for mutations in BRAF, NRAS and KRAS genes. We evaluated the relationship of identified variants with other clinical and biological features and determined the transcriptional signature associated with MAPK pathway activation in MM. To identify transcriptomic profiles possibly related to BRAF, NRAS and KRAS mutations found in our study, we investigated by Affymetrix microarray technology a large fraction (n=142) of the samples analyzed by NGS, including wild-type patients for all the three genes and cases carrying mutations in at least one of them. Assuming that alterations present in a very limited number of malignant PCs might not appreciably affect gene expression, we chose to arbitrarily establish 20% as the lower variant allele frequency cut-off to perform supervised analyses.
2015-07-01 | E-GEOD-66291 | biostudies-arrayexpress
Project description:Despite recent therapeutic advances in the management of BRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 17,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we identified a promising drug combination that efficiency kills 30% of melanoma cell lines. We validated in vivo the synergy of the drug combination and found a potential marker to identify sensitive tumors. We applied a genome-wide CRISPR screening which revealed that resistance mechanisms to the drug combination. In order to investigate the mechanism of drug synergy, we treated sensitive and resistance melanoma cell lines with the single drugs and the drug combination and performed proteome analyses to investigate the changes in total proteins and protein phosphorylation. These analysis highlighted specific pathway deregulations associated to the drug synergy that allowed to get a better understanding of the drug interaction and their efficacy in killing melanoma cell lines.
2022-03-23 | PXD007649 | Pride
Project description:We investigated copy number alterations in melanomas from two cohorts of Braf mutant mice (UV exposed and no UV exposure) by comparing tumour DNA to germline DNA by array CGH
2014-06-11 | GSE58265 | GEO