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Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma

Su, Yapeng and Lee, Jihoon W. and Ng, Rachel and Liu, Victoria and Peng, Songming and Xue, Min and Heath, James R. and Li, Guideng and Wong, Stephanie and Baltimore, David (2019) Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma. . (Unpublished)

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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.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Liu, Victoria0000-0003-1845-2497
Peng, Songming0000-0002-2742-6584
Heath, James R.0000-0001-5356-4385
Li, Guideng0000-0003-0840-7262
Baltimore, David0000-0001-8723-8190
Additional Information: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.
Funding AgencyGrant Number
NIHU01 CA217655
NIHU54 CA199090
NIHP01 CA168585
NIHR35 CA197633
Phelps Family FoundationUNSPECIFIED
Dr. Robert Vigen Memorial FundUNSPECIFIED
Ressler Family FundUNSPECIFIED
Ken and Donna SchultzUNSPECIFIED
Jean Perkins FoundationUNSPECIFIED
Institute for Systems BiologyUNSPECIFIED
National Key Research and Development Program of China2016YFC0900200
National Natural Science Foundation of China21775103
National Natural Science Foundation of China81672696
National Natural Science Foundation of China81772912
V Foundation-Gil Nickel Family Endowed FellowshipUNSPECIFIED
Sociedad Española de Oncología Médica (SEOM)UNSPECIFIED
Record Number:CaltechAUTHORS:20190805-155608943
Persistent URL:
Official Citation:Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma. Yapeng Su, Xiang Lu, Guideng Li, Chunmei Liu, Yan Kong, Jihoon Lee, Rachel Ng, Stephanie Wong, Lidia Robert, Charles Warden, Victoria Liu, Jie Chen, Zhuo Wang, YeziYapeng, Hanjun Cheng, Alphonsus Ng, Guangrong Qin, Songming Peng, Min Xue, DazyJohnson, Yu Xu, Jinhui Wang, Xiwei Wu, Ilya Shmulevich, Qihui Shi, Raphael Levine, Antoni Ribas, David Baltimore, Jun Guo, James R. Heath, Wei Wei. bioRxiv 724740; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:97667
Deposited By: Tony Diaz
Deposited On:05 Aug 2019 23:14
Last Modified:03 Oct 2019 21:33

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