CNV patterns in BRAFi resistant melanoma cell lines
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ABSTRACT:
PROVIDER: PRJNA471527 | ENA |
REPOSITORIES: ENA
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Project description:Genome variation profiling of BRAFi resistant melanoma cell lines comapered to the original ones by Affymetrix CytoScan 750K microarray
2019-01-31 | GSE114488 | GEO
Project description:The use of BRAF inhibitors, specific of the BRAFV600E mutation, as a therapeutic strategy for melanoma has significantly improved patient survival. However, resistance mechanisms appear systematically and limit the benefit of treatment. Here we show that AhR transcription factor participates in BRAFi resistance and is associated with the acquisition of an invasive and a dedifferentiated melanoma phenotype by controlling the expression of specific genes. AhR also induces the activation of the c-Src pathway through its phosphorylation, associated with BRAFi resistance. The use of a specific inhibitor of c-Src such as Dasatinib makes it possible to sensitize resistant cells to BRAFi and to prevent the acquisition of an invasive melanoma phenotype by regulating the expression of the AhR-dependent genes.
2022-10-18 | GSE166617 | GEO
Project description:The majority of BRAFV600 mutant melanomas regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). Yet nearly all relapse within the first two years. Most BRAFi/MEKi-resistant tumors are cross-resistant to immunotherapies, highlighting the need to prevent and circumvent resistance. We recently showed that androgen receptor (AR) activity is required for sustained melanoma cells proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells already at very early times of BRAFi exposure. Proliferation and tumorigenicity of BRAFi resistant melanoma cells are blunted by genetic or pharmacologic suppression of AR activity, while AR overexpression is by itself sufficient to rendersmelanoma cells BRAFi/MEKi-resistant. Increased AR elicits transcriptional changes linked with AXL-positive BRAFi resistant subpopulations and induces expression of PAI-1 and EGFR, two determinants of melanoma progression that associate with elevated AR expression in clinical cohorts. Our results point to increased AR signaling as a determinant of melanoma BRAFi resistance, which can be counteracted by AR as well as PAI-1 and EGFR inhibitors.
2023-08-03 | GSE232693 | GEO
Project description:The majority of BRAFV600 mutant melanomas regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). Yet nearly all relapse within the first two years. Most BRAFi/MEKi-resistant tumors are cross-resistant to immunotherapies, highlighting the need to prevent and circumvent resistance. We recently showed that androgen receptor (AR) activity is required for sustained melanoma cells proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells already at very early times of BRAFi exposure. Proliferation and tumorigenicity of BRAFi resistant melanoma cells are blunted by genetic or pharmacologic suppression of AR activity, while AR overexpression is by itself sufficient to rendersmelanoma cells BRAFi/MEKi-resistant. Increased AR elicits transcriptional changes linked with AXL-positive BRAFi resistant subpopulations and induces expression of PAI-1 and EGFR, two determinants of melanoma progression that associate with elevated AR expression in clinical cohorts. Our results point to increased AR signaling as a determinant of melanoma BRAFi resistance, which can be counteracted by AR as well as PAI-1 and EGFR inhibitors.
2023-08-03 | GSE199405 | GEO
Project description:The majority of BRAFV600 mutant melanomas regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). Yet nearly all relapse within the first two years. Most BRAFi/MEKi-resistant tumors are cross-resistant to immunotherapies, highlighting the need to prevent and circumvent resistance. We recently showed that androgen receptor (AR) activity is required for sustained melanoma cells proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells already at very early times of BRAFi exposure. Proliferation and tumorigenicity of BRAFi resistant melanoma cells are blunted by genetic or pharmacologic suppression of AR activity, while AR overexpression is by itself sufficient to rendersmelanoma cells BRAFi/MEKi-resistant. Increased AR elicits transcriptional changes linked with AXL-positive BRAFi resistant subpopulations and induces expression of PAI-1 and EGFR, two determinants of melanoma progression that associate with elevated AR expression in clinical cohorts. Our results point to increased AR signaling as a determinant of melanoma BRAFi resistance, which can be counteracted by AR as well as PAI-1 and EGFR inhibitors.
2023-08-03 | GSE232690 | GEO
Project description:Acquired resistance to MAPK inhibitors limits the clinical efficacy in melanoma treatment. We and others have recently shown that BRAF inhibitors (BRAFi)-resistant melanoma cells can develop a dependency on the therapeutic drugs to which they have acquired resistance, creating a vulnerability for these cells that can potentially be exploited in cancer treatment. In drug addicted melanoma cells, it was shown that this induction of cell death was preceded by a specific ERK2-dependent phenotype switch, however, the underlying molecular mechanisms are largely lacking. To increase the molecular understanding of this drug dependency, we applied a mass spectrometry-based proteomic approach on BRAFi-resistant BRAFMUT 451Lu cells, in which ERK1, ERK2 and JUNB were silenced separately using CRISPR–Cas9. Inactivation of ERK2 and, to a lesser extent, JUNB prevents drug addiction in these melanoma cell while, conversely, knock out of ERK1 fails to reverse this phenotype, showing a response similar to control cells. Our analysis reveals that ERK2 and JUNB share comparable proteome responses dominated by reactivation of cell division. Importantly, we find that EMT activation in drug addicted melanoma cells upon drug withdrawal is affected by silencing ERK2 but not ERK1. Moreover, transcription factor (regulator) enrichment shows that PIR acts as an effector of ERK2 and phosphoproteome analysis reveals that silencing of ERK2 but not ERK1 leads to amplification of GSK3 kinase activity. Our results depict possible mechanisms of drug addiction in melanoma, which may provide a guide for strategies in drug-resistant melanoma.
2022-02-17 | PXD026557 | Pride
Project description:Treatment of advanced V600BRAF mutant melanoma using a BRAF inhibitor (BRAFi) or its combination with a MEKi typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPKi therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or -positive fractions,, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK-dependency, while enhancing mesenchymal, angiogenic and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.
2017-09-12 | GSE103688 | GEO
Project description:Treatment of advanced V600BRAF mutant melanoma using a BRAF inhibitor (BRAFi) or its combination with a MEKi typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPKi therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or -positive fractions,, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK-dependency, while enhancing mesenchymal, angiogenic and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.
2017-09-12 | GSE103687 | GEO
Project description:Most BRAF-mutant melanoma tumors respond initially to BRAFi/MEKi therapy, although few patients have durable long-term responses to these agents. The goal of this study was to utilize an unbiased computational approach to identify inhibitors which reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we predicted that ibrutinib, a BTK inhibitor, effectively reverses this signature, and we demonstrate experimentally that ibrutinib re-sensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as a BTK inhibitor; however, neither BTK deletion nor treatment with acalabrutinib, an analog of ibrutinib with reduced off-target activity, re-sensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib re-sensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple SRC kinase inhibitors. Since ibrutinib, but not acalabrutinib, has significant off-target activity against multiple SRC family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes either upregulated or downregulated by ibrutinib treatment are enriched with YAP1 target genes and we experimentally demonstrate that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other SRC family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors.
2020-02-27 | GSE145990 | GEO
Project description:Pre- and post-BRAFi melanoma FFPE samples were macrodissected for enrichment of tumor cellularity and analyzed for gene expression to identify transcriptional changes related to resistance to BRAFi therapy
2020-10-02 | GSE141484 | GEO