Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA380061 | ENA |
REPOSITORIES: ENA
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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
Project description:3 BRAF/MEK inhibitor resistance melanoma cells were treated with PAK inhibitor PF3758309 for 48 hr, the cell lysis were analyzed by RPPA profiling by protein array (RPPA)
2017-07-31 | GSE96902 | GEO
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.
2018-04-18 | GSE110948 | GEO
Project description:Rapid resistance to BRAF inhibitors in BRAFV600-mutant metastatic melanoma has produced an urgent need for new treatment options. BRAF inhibitor resistance commonly involves reactivation of mitogen-activated protein kinase (MAPK) signaling and yet inhibition of downstream kinases has not circumvented resistance, partly because MAPK is regulated via a complex network of feedback mechanisms that influence pathway rebound. To examine the transcriptome responses of melanoma cells to MAPK inhibition, a panel of 11 BRAFV600-mutant melanoma cell lines were treated with control (DMSO), 100nM dabrafenib alone (i.e BRAF inhibitor monotherapy) or 100nM dabrafenib + 10nM trametinib (i.e combination BRAF + MEK inhibition) for 24h.
2017-09-20 | GSE98314 | GEO
Project description:protein levels in BRAF inhibitor resistance melanoma cells treated with PF3758309
| PRJNA379575 | ENA
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
Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.
2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress
Project description:Using a chromatin regulator-focused shRNA library, we found that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes resistance to BRAF and MEK inhibitors. To investigate how SOX10 loss leads to drug resistance, we performed transcriptome sequencing (RNAseq) of both parental A375 (Ctrl. PLKO) and A375-SOX10KD (shSOX10-1, shSOX10-2) cells. To ask directly whether SOX10 is involved indrug resistance in BRAF(V600E) melanoma patients, we isolated RNA from paired biopsies from melanoma patients (pre- and post- treatment) , that had gained BRAF or MEK inhibitor resistance . We performed RNAseq analysis to determine changes in transcriptome upon drug resistance.
2014-01-04 | GSE50535 | GEO
Project description:BRAFV600E mutant melanomas treated with BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) almost invariably develop drug resistance (DTR). Restored glycolysis, frequently found in clinical targeted therapy-resistant melanoma biopsies, has been shown to elicit drug resistance. How resumed glycolysis controls the emergence of acquired resistance, especially via intrinsic mechanisms that circumvent the BRAF/MEK module, remains unknown. Here, we identify lactylation of LSD1, induced by re-accumulated lactate in DTR melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with FosL1, thereby preventing its ubiquitination and degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21). In DTR melanoma cells, chromatin binding capacity of FosL1 was significantly strengthened due to reduced acetylation, which in turn increases selective chromatin enrichment of LSD1. We further demonstrate that lactylated LSD1 co-orchestrates gene transcription with FosL1 to repress ferroptosis in DTR cells via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibitor (LSD1i) activates ferroptosis, resulting in drastic DTR melanoma regression in mice. Importantly, LSD1i-induced immunogenic ferroptosis synergizes with immune checkpoint blockade (ICB) in vivo. Together, our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in DTR melanoma, which provides a therapeutically actionable strategy to overcome acquired resistance to targeted therapy.
2025-02-13 | GSE256123 | GEO
Project description:BRAFV600E mutant melanomas treated with BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) almost invariably develop drug resistance (DTR). Restored glycolysis, frequently found in clinical targeted therapy-resistant melanoma biopsies, has been shown to elicit drug resistance. How resumed glycolysis controls the emergence of acquired resistance, especially via intrinsic mechanisms that circumvent the BRAF/MEK module, remains unknown. Here, we identify lactylation of LSD1, induced by re-accumulated lactate in DTR melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with FosL1, thereby preventing its ubiquitination and degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21). In DTR melanoma cells, chromatin binding capacity of FosL1 was significantly strengthened due to reduced acetylation, which in turn increases selective chromatin enrichment of LSD1. We further demonstrate that lactylated LSD1 co-orchestrates gene transcription with FosL1 to repress ferroptosis in DTR cells via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibitor (LSD1i) activates ferroptosis, resulting in drastic DTR melanoma regression in mice. Importantly, LSD1i-induced immunogenic ferroptosis synergizes with immune checkpoint blockade (ICB) in vivo. Together, our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in DTR melanoma, which provides a therapeutically actionable strategy to overcome acquired resistance to targeted therapy.
2025-02-13 | GSE256122 | GEO