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Published August 5, 2019 | Submitted
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Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma


We resolved a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, with MAPK inhibition of BRAF-mutant melanomas providing the model. These cancer cells undergo multiple, reversible drug-induced cell-state transitions, ultimately yielding a drug-resistant mesenchymal-like phenotype. A kinetic series of transcriptome and epigenome data, collected over two months of drug treatment and release, revealed changing levels of thousands of genes and extensive chromatin remodeling. However, a 3-step computational algorithm greatly simplified the interpretation of these changes, and revealed that the whole adaptive process was controlled by a gene module activated within just three days of treatment, with RelA driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. These findings were confirmed across several patient-derived cell lines and in melanoma patients under MAPK inhibitor treatment. Co-targeting BRAF and histone-modifying enzymes arrests adaptive transitions towards drug tolerance in epigenetically plastic melanoma cells and may be exploited therapeutically.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv preprint first posted online Aug. 5, 2019. We thank S. Huang (ISB) and L. Hood (ISB) for comments on the manuscript. We acknowledge the following funding agencies and foundations for support: NIH/NCI U01 CA217655 (to R.L., A.R., J.R.H., and W.W.), U54 CA199090 (to A.R., J.R.H., and W.W.), P01 CA168585 (to A.R.), R35 CA197633 (to A.R.), Andy Hill CARE Fund (to W.W.), and Phelps Family Foundation (to W.W.); Dr. Robert Vigen Memorial Fund, the Ressler Family Fund, and Ken and Donna Schultz (A.R.); the Jean Perkins Foundation (J.R.H.); ISB Innovator Award (Y.S.). National Key Research and Development Program Grant 2016YFC0900200 (to Q.S.), National Natural Science Foundation of China Grant 21775103 (to Q.S.), 81672696 (to J.G.), and 81772912 (to Y.K.). L.R. was supported by the V Foundation-Gil Nickel Family Endowed Fellowship and a scholarship from SEOM. Author Contributions: J.R.H. and W.W. conceived the project and supervised the study. Y.S., X.L., G.L., C.L., R.N., S.W., L.R., V.L., V.L., J.C., Z.W., H.C., A.H.C.N., S.P., M.X., D.J., and J.W. performed the experiments. X.L., C.L., and C.W. performed bioinformatics analysis. Y.S., X.L., R.L., J.R.H., and W.W. established the computational models. Y.S., X.L., G.L., C.L., J.W.L., C.W., V.L., Z.W., Y.Y., G.Q., J.W., I.S., X.W., Q.S., R.L., A.R., D.B., J.G., J.R.H., and W.W. analyzed the data. Y.K., Y.X., and J.G. contributed the clinical specimens and expertise. Y.S., X.L., J.R.H., and W.W. wrote the paper. Everyone reviewed the paper. The authors declare no competing interests. Data and Software Availability: The accession number for the gene expression, ATAC-seq and ChIP-seq data reported in this paper is GEO: GSE134459.

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