Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA218009 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes. Total RNA was obtained from fresh-frozen melanoma tumour samples from patients before commencing treatment with dabrafenib or vemurafenib and at time of tumour progression.
2014-02-19 | E-GEOD-50509 | biostudies-arrayexpress
Project description:Genotype directed anti-cancer therapies such BRAF inhibitor in BRAF mutant melanoma can show remarkable clinical efficacy but resistance limits their benefit. We show that a transposon activation screen efficiently identifies resistance genes to BRAF and captures a number of previously uncharacterized resistance mechanisms, including an E3 ubiquitin ligase NEDD4L and the Hippo pathway effector WWTR1 (TAZ). Resistance can be reversed by combining BRAF inhibition with tyrosine kinase inhibitors as observed previously for other resistance genes. Moreover, an integrative analysis of several gain- and loss-of-function genetic screens performed in the same context reveals smaller functional diversity of resistance mechanisms to MAPK inhibition than suggested by the broad range of resistance genes identified, implying common therapeutic strategies. A375 cells with lentiviral vector controls or WWTR1 cDNA plasmid.
2016-07-01 | E-GEOD-73470 | biostudies-arrayexpress
Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.
2017-03-06 | E-MTAB-5511 | biostudies-arrayexpress
Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.
2017-03-06 | E-MTAB-5510 | biostudies-arrayexpress
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:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes.
2014-02-19 | GSE50509 | GEO
Project description:Genotype directed anti-cancer therapies such BRAF inhibitor in BRAF mutant melanoma can show remarkable clinical efficacy but resistance limits their benefit. We show that a transposon activation screen efficiently identifies resistance genes to BRAF and captures a number of previously uncharacterized resistance mechanisms, including an E3 ubiquitin ligase NEDD4L and the Hippo pathway effector WWTR1 (TAZ). Resistance can be reversed by combining BRAF inhibition with tyrosine kinase inhibitors as observed previously for other resistance genes. Moreover, an integrative analysis of several gain- and loss-of-function genetic screens performed in the same context reveals smaller functional diversity of resistance mechanisms to MAPK inhibition than suggested by the broad range of resistance genes identified, implying common therapeutic strategies.
2016-07-01 | GSE73470 | GEO
Project description:Increased MITF expression contributes to melanoma progression and resistance to BRAF pathway inhibition. We show that, unexpectedly, lack of MITF is associated with more severe resistance to a range of inhibitors. Indeed, the presence of endogenous MITF was essential for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlated with expression of several activated receptor tyrosine kinases, most commonly AXL. The MITF-low/AXL-high/drug resistance phenotype was seen in roughly half of BRAF mutant and the majority of NRAS mutant melanoma cell lines. The dichotomous behavior of MITF in drug response was corroborated in vemurafenib-resistant biopsies, including MITF high and low clones in a relapsed patient. Drug cocktails containing AXL inhibitor enhanced melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. Experssion analysis by RNAseq of 14 melanoma cell lines.
2014-09-19 | E-GEOD-61544 | biostudies-arrayexpress
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
Project description:Human melanoma samples were collected pre, on, and progression on BRAF inhibitor therapy. RNA was extracted and run on RNA-seq. This has provided insights into different categories of BRAF inhibitor resistance mechanisms.
| EGAS00001000992 | EGA