Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma
75 Pages Posted: 21 Aug 2019 Sneak Peek Status: Under ReviewMore...
We resolve a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, using MAPK inhibition of BRAF-mutant melanomas as a model. These cancer cells adapt to MAPK inhibitors through reversible transitions towards a drug-resistant mesenchymal phenotype. Transcriptome and epigenome kinetics studies revealed extensive gene expression alterations and chromatin remodeling. A 3-step algorithm revealed that the adaptive process was controlled by a fast-acting gene module, with RelA driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. These finding were confirmed across melanoma cell lines and patients. Co-targeting BRAF and histone-modifying enzymes arrested adaptive transitions towards drug tolerance. Our findings highlight the importance of epigenetic plasticity in therapeutic resistance and resolve the mechanistic network driving this process.
Keywords: non-genetic drug resistance, epigenetic plasticity, chromatin remodeling, melanoma, targeted therapy resistance, multi-omics characterization, systems biology, information theory, dynamic systems, histone modification
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