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Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping
Yuanyuan Kang1, Zhenyu Ji1, He Li2
1Wellman Center for Photomedicine, Mass General Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Although tremendous progress has been made in targeted and immune-based treatments for advanced melanoma, there remains a substantial therapeutic failure rate. For patients with BRAF(V600)-mutant melanomas, resistance to BRAF inhibitors remains a significant survival hurdle. Although multiple compensatory mechanisms to bypass BRAF blockade have been discovered, the epigenetic patterns are still poorly characterized. In this report, we generated eight matched pairs of vemurafenib-sensitive/-resistant melanoma lines and subjected these to concurrent RNA-sequencing and H3K27ac chromatin immunoprecipitation sequencing 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 epithelial‒mesenchymal transition and hypoxia-related pathways. We also observed significant and dynamic changes in superenhancers that underpin these transcriptomic patterns. We subsequently verified the two-class structure in pre-BRAF inhibitors and postrelapse human melanoma specimens. Our findings reveal a broad and underappreciated spectrum of epigenetic plasticity during acquired BRAF inhibitor resistance.
Insights
Acquired resistance to BRAF inhibitors in melanoma involves two distinct epigenetic profiles. These patterns, characterized by changes in gene expression and enhancer activity, offer new insights into therapeutic failure in melanoma treatment.
Area of Science:
- Cancer Biology
- Epigenetics
- Melanoma Research
Background:
- Advanced melanoma treatments, including targeted and immune therapies, still face significant failure rates.
- Resistance to BRAF inhibitors is a major challenge for patients with BRAF(V600)-mutant melanomas.
- While compensatory mechanisms for BRAF blockade are known, epigenetic alterations driving resistance are not well understood.
Purpose of the Study:
- To investigate the epigenetic patterns associated with acquired resistance to BRAF inhibitors in melanoma.
- To characterize the transcriptional and enhancer profile changes contributing to vemurafenib resistance.
- To identify potential therapeutic vulnerabilities linked to epigenetic plasticity in resistant melanoma.
Main Methods:
- Generated eight matched pairs of vemurafenib-sensitive and -resistant melanoma cell lines.
- Performed concurrent RNA-sequencing and H3K27ac chromatin immunoprecipitation sequencing.
- Analyzed epigenetic profiles and transcriptional alterations in resistant melanoma models and human specimens.
Main Results:
- Identified two distinct classes of epigenetic profiles correlating with BRAF inhibitor resistance.
- Class 1 resistance showed minimal RNA expression and H3K27ac changes.
- Class 2 resistance exhibited widespread transcriptional and enhancer alterations, converging on epithelial-mesenchymal transition and hypoxia pathways.
- Observed dynamic superenhancer changes underlying transcriptomic patterns in resistant melanomas.
Conclusions:
- Acquired BRAF inhibitor resistance in melanoma is associated with a spectrum of epigenetic plasticity.
- Two distinct epigenetic resistance classes, differing in the extent of transcriptional and enhancer alterations, were identified.
- Findings highlight the underappreciated role of epigenetics in melanoma treatment failure and suggest potential therapeutic targets.
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