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Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203546 | GEO | 2022/05/25

REPOSITORIES: GEO

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Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping

Project description:In this report, we generated eight matched pairs of vemurafenib sensitive/resistant melanoma lines and subjected these to concurrent RNA-seq and H3K27Ac ChIP-seq analysis. Globally, we identified two classes of epigenetic profiles that correlate with resistance. Class 1 resistance involves fewer RNA expression alterations accompanied by fewer enhancer mark changes with H3K27Ac. Class 2 resistance shows widespread alterations in transcription and enhancer profiles, which converge on EMT and hypoxia-related pathways. We also observed significant and dynamic changes in super-enhancers that underpin these transcriptomic patterns. We subsequently verified the 2-class structure in pre-BRAFi and post-relapse human melanoma specimens. Our findings reveal a broad and underappreciated spectrum of epigenetic plasticity during acquired BRAFi resistance.

2022-05-25 | GSE203544 | GEO

Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping [RNA-seq]

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Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping

Project description:Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping

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Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping [ChIP-seq]

Project description:Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping [ChIP-seq]

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Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping [RNA-seq]

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The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.

Project description: Not available

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

Project description: Not available

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Epigenetic reprogramming in adaptive drug resistance to BRAF inhibitor therapy

Project description:The development of drug resistance is a major limiting factor to the efficacy of BRAF inhibitor therapy for melanoma. The goal of this study was to identify and characterize pathways that contribute to adaptive drug resistance to BRAF inhibitors.

2021-12-31 | GSE156302 | GEO

Spectrum, clinical correlates and clinical implications of BRAF-inhibitor resistance mechanisms in melanoma

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

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