Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA198428 | ENA |
REPOSITORIES: ENA
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Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi. Expression of WNT5A-correlated genes was compared in melanoma cell lines generated to be resistant to PLX4032 and the their associated naïve parental line Basal expression of the WNT5A-correlated genes was also measured in experiments comparing each naïve line to a mixed reference pool containing equal amounts of 47 melanoma cell lines.
2014-03-06 | E-GEOD-55583 | biostudies-arrayexpress
Project description:Differential gene expression analysis of parental and resistant sub-lines of melanoma cell lines treated or untreated with PLX4032 Using microarray we sought to obtain a genome-wide profile of differentially expressed genes in parental melanoma cell lines and resistant sub-lines in response to PLX4032 vs DMSO control treatment.
2010-11-26 | GSE24862 | GEO
Project description:aCGH of human melanoma cell lines comparing parental (drug sensitve) vs isogenic drug resistant-derived subline
2014-04-21 | GSE49430 | GEO
Project description:CNV patterns in BRAFi resistant melanoma cell lines
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Project description:Differential gene expression analysis of parental and resistant sub-lines of melanoma cell lines treated or untreated with PLX4032 Using microarray we sought to obtain a genome-wide profile of differentially expressed genes in parental melanoma cell lines and resistant sub-lines in response to PLX4032 vs DMSO control treatment. Representative parental melanoma cell lines and resistant sub-lines were treated with PLX4032 at 1 uM or DMSO control for 6h. Total RNA was extracted and cDNAs were generated and hybridized onto GeneChip Human Gene 1.0 ST Arrays (Affymetrix).
2010-11-26 | E-GEOD-24862 | biostudies-arrayexpress
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: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
Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi.
2014-03-06 | GSE55583 | GEO
Project description:To investigate mechanisms of resistance to BRAF inhibitor therapy in melanoma, BRAF mutant cell lines have been chronically exposed to BRAFi to create phenotypes with acquired drug resistance. Expression proteomics is used to examine the differences between naive and drug-resistant cells.
2016-12-13 | PXD004342 | Pride
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