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RNA Seq data: A375, A375R, A375DR vorinostat treated, and biopy samples from patients pre- and post- treated with Vorinostat

ABSTRACT: BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110948 | GEO | 2018/04/18

REPOSITORIES: GEO

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DNA Seq data: biopy samples from patients pre- and post- treated with Vorinostat

Project description:BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here. DNA Seq data: biopy samples from patients pre- and post- treated with Vorinostat; check mutations related to MAPKi-resistance

2018-04-18 | GSE111140 | GEO

Expression data from BRAF-mutant melanoma cell lines

Project description:Melanoma cell lines were assessed for differences in gene expression patterns between the lines sensitive and resistant to BRAF and MEK inhibitor drugs. 22 BRAF-mutant melanoma cell lines were assessed for response to BRAF and MEK inhibitors in a 3 day drug treatment dose response assay. Based on the IC50, 18 lines were found to be responsive to BRAF or MEK inhibition and 4 were resistant. Normalised gene expression data generated from experimental replicate affymetrix arrays was assessed to identify differential patterns of inherent gene expression between the cell lines grouped as drug-responsive or drug-resistant. This were used to idenify specific candidate genes and pathways associated with inherent BRAF/MEK inhibitor drug resistance in melanoma cells.

2015-08-26 | E-GEOD-45558 | biostudies-arrayexpress

Human BRAF-V600E melanoma cell lines drug sensitive vs drug resistant

Project description:aCGH of human melanoma cell lines comparing parental (drug sensitve) vs isogenic drug resistant-derived subline Two condition experiment: two BRAF-V600E mutant cell lines (drug sensitive - parental baseline) vs two derived sublines after chronic exposure to the MEK inhibitor trametinib (drug resistant) are compared

2014-04-21 | E-GEOD-49430 | biostudies-arrayexpress

Anti-proliferative effects of continued mitogen activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma: Implications for treatment beyond disease progression

Project description:Inhibitors of the MAPKs, BRAF and MEK, induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6-7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now demonstrate that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signalling, decrease in BrdU incorporation and S-phase inhibition. This cytostatic effect was also associated diminished levels of cyclin D1 and p-pRb.. Two short-term melanoma cultures generated from resistant tumour biopsies also responded to MAPK inhibition with comparable inhibitory changes in proliferation and MAPK signalling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. Total RNA obtained from melanooma cell lines treated for 24h with dabrafenib, trametinib or combination of dabrafenib and trametinib

2013-06-30 | E-GEOD-44753 | biostudies-arrayexpress

Predominance of MAPK reactivation in early resistance to debrafenib/trametinib combination therapy of BRAF mutant metastatic melanoma.

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

Differential patterns of protein expression in monolayer or spheroid melanoma cell models of acquired resistance to BRAF and MEK1/2 inhibitors

Project description:Mitogen activated protein kinase (MAPK) inhibitors are important therapies for treating many cancers. However, the development of acquired resistance to most protein kinase inhibitors limit their ability to provide durable responses. Approximately 50% of malignant melanomas contain activating mutations in the BRAF kinase, which promote cancer cell survival by activating the extracellular signal-regulated kinase-1/2 (ERK1/2) pathway through direct phosphorylation of the MAPK/ERK kinase-1/2 (MEK1/2). Although combination treatment with BRAF and MEK1/2 inhibitors is a recommended approach to treat melanoma, the development of drug resistance remains a barrier to achieving long term patient benefits. Using high-resolution label-free mass spectrometry, the current studies compared relative protein changes in BRAF and MEK1/2 inhibitor resistant A375 melanoma cells grown as monolayers or 3D spheroids. While approximately 66% of proteins identified were common in both monolayer and spheroid cultures, only 6.2% or 3.6% of proteins that significantly increased or decreased, respectively, compared to drug sensitive cells were common between the drug-resistant monolayer and spheroid cells. Major changes in drug-resistant monolayers suggested upregulation of alternative kinase signaling pathways that promote growth and metastasis. In contrast, the major changes in drug-resistant spheroids indicated increased catabolic metabolism to support oxidative phosphorylation and energy requirements.

2022-02-17 | PXD026952 | Pride

RNAseq changes in mouse wound with or without time course treatment by Vemurafenib

Project description:BRAF inhibitors are highly effective therapies for patients with BRAF V600 mutated metastatic melanoma. Patients who receive BRAF inhibitors develop a variety of hyper-proliferative skin conditions, whose pathogenic basis is the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyper-proliferative skin changes improve when a MEK inhibitor is co-administered, as a MEK inhibitor blocks paradoxical MAPK activation. We tested whether we could take advantage of the mechanistic understanding of the skin hyper-proliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation. Here we show that the BRAF inhibitor vemurafenib accelerates human keratinocyte proliferation and migration by increasing ERK phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing models in mice accelerated cutaneous wound healing and improved the tensile strength of healing wounds through paradoxical MAPK activation; addition of a MEK inhibitor reversed the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor did not increase the incidence of cutaneous squamous cell carcinomas in mice even after the application of a carcinogen. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. Full depth incisional wound mice tissues with/without Vemurafenib treatment were sent for RNAseq analysis on day 2, 6 and 14

2016-07-29 | E-GEOD-74558 | biostudies-arrayexpress

BRAF siRNA NHGRI_Liang_BRAF

Project description:BRAF, one of three RAF serine/threonine kinases (ARAF, BRAF and CRAF), plays a major role in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway, which mediates cellular responses to growth signals. Recently a high frequency (~60%-70%) of activating BRAF mutations (predominantly V600E) has been reported in malignant melanoma. In order to identify the downstream effects of BRAF signaling on melanoma cell growth and gene expression, cDNA microarray analysis was carried out following BRAF siRNA or MEK1/2 inhibitor (U0126) treatment. Keywords: time series, siRNA time series, siRNA, drug treatment

2013-07-07 | E-GEOD-5481 | biostudies-arrayexpress

HDAC8 regulates escape from BRAF inhibitor therapy in Melanoma: IMAC Phosphoproteomics

Project description:Melanoma cells are highly plastic and have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanoma cell lines and patient specimens to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia and UV-irradiation leads to an increase in histone deacetylase 8 (HDAC8) expression/activity, and in turn, the adoption of a drug-resistant, invasive phenotype. Systems level analyses using mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling pathways. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both in vitro and in in vivo xenograft models. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase (RTK) activation leading to Ras/CRAF/MEK/ERK signaling. Although HDACs primarily function at the histone level, they also regulate signaling through the modulation of non-histone substrates. In line with this, HDAC8 introduction decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine residue 273 reduced the transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition through increased RTK expression and enhanced MAPK pathway activity. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both non-selective and HDAC8-specific inhibitors enhancing the durability of response to BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors could represent an excellent strategy to limit the adaptation of melanoma cells to multiple stresses and therapeutic interventions, including BRAF-MEK inhibitor combinations.

2020-07-07 | PXD012813 | Pride

HDAC8 regulates escape from BRAF inhibitor therapy in Melanoma: Phosphotyrosine Profiling

2020-07-07 | PXD012812 | Pride

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