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Melanoma cell acquired resistance to vinca-alkaloids

ABSTRACT: Malignant melanoma (MM) remains a therapeutic challenge on account of extreme primary resistance to apoptosis and fated acquired chemoresistance. In the current context of molecular classification of MM, the understanding of molecular mechanisms giving rise to these resistances should drive therapeutic choice trough personalized medicine. In order to study mechanisms of MM acquire resistance to VAs, we previously established three VA-resistant cell lines, CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB, by long time exposure of the CAL1-wt MM cell line to IC50 (4nM) of VCR, VDS and VRB respectively. CAL1R-VAs cell lines consisted of polyclonal populations to respect biological diversity of tumour. Then, we searched for determine the resistance process impact on MM cells. We thus performed genome-wide analyses based on comparison of global transcriptomic profile of CAL1R-VAs cells to CAL1-wt. In this way, RNA extracted from each cell line was hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. After hybridization, microarray data were processed with Robust Multi-array Average (RMA) algorithm. We then performed bioinformatic analyses of microarray data and in vitro investigations in the aim to identify genes and pathways that might predict drug resistance. Melanoma model: CAL1 cell line. Treatments: vinorelbine (VRB), vincristine (VCR), vindesine (VDS). Etablishment of 3 resistant cell lines by long time exposure to vinka-alkaloids (4nM, 6-12 months): CAL1R-VRB, CAL1R-VCR, CAL1R-VDS. RNA extracted from a pooled population of each cell line were hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. Then, microarray data were processed with Robust Multi-array Average (RMA) algorithm.

ORGANISM(S): Homo sapiens

SUBMITTER: Vincent Laure-Anais

PROVIDER: S-ECPF-GEOD-61007 | biostudies-other |

REPOSITORIES: biostudies-other

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Melanoma cell acquired resistance to vinca-alkaloids

Project description:Malignant melanoma (MM) remains a therapeutic challenge on account of extreme primary resistance to apoptosis and fated acquired chemoresistance. In the current context of molecular classification of MM, the understanding of molecular mechanisms giving rise to these resistances should drive therapeutic choice trough personalized medicine. In order to study mechanisms of MM acquire resistance to VAs, we previously established three VA-resistant cell lines, CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB, by long time exposure of the CAL1-wt MM cell line to IC50 (4nM) of VCR, VDS and VRB respectively. CAL1R-VAs cell lines consisted of polyclonal populations to respect biological diversity of tumour. Then, we searched for determine the resistance process impact on MM cells. We thus performed genome-wide analyses based on comparison of global transcriptomic profile of CAL1R-VAs cells to CAL1-wt. In this way, RNA extracted from each cell line was hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. After hybridization, microarray data were processed with Robust Multi-array Average (RMA) algorithm. We then performed bioinformatic analyses of microarray data and in vitro investigations in the aim to identify genes and pathways that might predict drug resistance. Melanoma model: CAL1 cell line. Treatments: vinorelbine (VRB), vincristine (VCR), vindesine (VDS). Etablishment of 3 resistant cell lines by long time exposure to vinka-alkaloids (4nM, 6-12 months): CAL1R-VRB, CAL1R-VCR, CAL1R-VDS. RNA extracted from a pooled population of each cell line were hybridized to Affimetrix HG-U133 Plus 2.00 GeneChips. Then, microarray data were processed with Robust Multi-array Average (RMA) algorithm.

2014-09-03 | E-GEOD-61007 | biostudies-arrayexpress

Melanoma cell acquired resistance to vinca-alkaloids

2014-09-03 | GSE61007 | GEO

Clinical Implications of Acquired BRAF Inhibitors Resistance in Melanoma.

Project description:Understanding the role of mitogen-activated protein kinase (MAPK) pathway-activating mutations in the development and progression of melanoma and their possible use as therapeutic targets has substantially changed the management of this neoplasm, which, until a few years ago, was burdened by severe mortality. However, the presence of numerous intrinsic and extrinsic mechanisms of resistance to BRAF inhibitors compromises the treatment responses' effectiveness and durability. The strategy of overcoming these resistances by combination therapy has proved successful, with the additional benefit of reducing side effects derived from paradoxical activation of the MAPK pathway. Furthermore, the use of other highly specific inhibitors, intermittent dosing schedules and the association of combination therapy with immune checkpoint inhibitors are promising new therapeutic strategies. However, numerous issues related to dose, tolerability and administration sequence still need to be clarified, as is to be expected from currently ongoing trials. In this review, we describe the clinical results of using BRAF inhibitors in advanced melanoma, with a keen interest in strategies aimed at overcoming resistance.

| S-EPMC7766699 | biostudies-literature

Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions.

Project description:Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8+ T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.

| S-EPMC5460020 | biostudies-literature

Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma.

Project description:The discovery of activating BRAF V600E mutations in 50% of all cutaneous melanomas has revolutionized the understanding of melanoma biology and provided new strategies for the therapeutic management of this deadly disease. Highly potent small molecule inhibitors of BRAF are now showing great promise as a novel therapeutic strategy for melanomas harboring activating BRAF V600E mutations and are associated with high levels of response. This commentary article discusses the latest data on the role of mutated BRAF in the development and progression of melanoma as the basis for understanding the mechanism of action of BRAF inhibitors in the preclinical and clinical settings. We further address the issue of BRAF inhibitor resistance and outline the latest insights into the mechanisms of therapeutic escape as well as describing approaches to prevent and abrogate the onset of both intrinsic and acquired drug resistance. It is likely that our evolving understanding of melanoma genetics and signaling will allow for the further personalization of melanoma therapy with the goal of improving clinical responses.

| S-EPMC4001781 | biostudies-literature

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review.

Project description:This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of 'escape routes', so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

| S-EPMC7600801 | biostudies-literature

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.

Project description:BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.

| S-EPMC3936420 | biostudies-literature

AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma.

Project description:An activating BRAF (V600E) kinase mutation occurs in approximately half of melanomas. Recent clinical studies have demonstrated that vemurafenib (PLX4032) and dabrafenib, potent and selective inhibitors of mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF), exhibit remarkable activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after the initial treatment. Identification of acquired resistance mechanisms may inform the development of new therapies that elicit long-term responses of melanomas to BRAF inhibitors. Here we report that increased expression of AEBP1 (adipocyte enhancer-binding protein 1) confers acquired resistance to BRAF inhibition in melanoma. AEBP1 is shown to be highly upregulated in PLX4032-resistant melanoma cells because of the hyperactivation of the PI3K/Akt-cAMP response element-binding protein (CREB) signaling pathway. This upregulates AEBP1 expression and thus leads to the activation of NF-κB via accelerating IκBa degradation. In addition, inhibition of the PI3K/Akt-CREB-AEBP1-NF-κB pathway greatly reverses the PLX4032-resistant phenotype of melanoma cells. Furthermore, increased expression of AEBP1 is validated in post-treatment tumors in patients with acquired resistance to BRAF inhibitor. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-κB pathway whose activation contributes to acquired resistance to BRAF inhibition, and suggest that this pathway, particularly AEBP1, may represent a novel therapeutic target for treating BRAF inhibitor-resistant melanoma.

| S-EPMC3847319 | biostudies-literature

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.

Project description:BackgroundApproximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.MethodsWe analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.ResultsWhole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.ConclusionsIn this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

| S-EPMC5007206 | biostudies-literature

IL-1α Mediates Innate and Acquired Resistance to Immunotherapy in Melanoma.

Project description:Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.

| S-EPMC8023145 | biostudies-literature

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