University of California, Los Angeles (UCLA) - Department of Medicine; University of California, Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center
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
Su, Yapeng and Lu, Xiang and Li, Guideng and Liu, Chunmei and Kong, Yan and Lee, Jihoon W. and Ng, Rachel and Wong, Stephanie and Robert, Lidia and Warden, Charles and Liu, Victoria and Chen, Jie and Wang, Zhuo and Yang, Yezi and Cheng, Hanjun and Ng, Alphonsus H.C. and Qin, Guangrong and Peng, Songming and Xue, Min and Johnson, Dazy and Xu, Yu and Wang, Jinhui and Wu, Xiwei and Shmulevich, Ilya and Shi, Qihui and Levine, Raphael and Ribas, Antoni and Baltimore, David and Guo, Jun and Heath, James R. and Wei, Wei, Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma (August 20, 2019). Available at SSRN: https://ssrn.com/abstract=3439668 or http://dx.doi.org/10.2139/ssrn.3439668
This version of the paper has not been formally peer reviewed.
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