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Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma

75 Pages Posted: 21 Aug 2019 Sneak Peek Status: Under Review

See all articles by Yapeng Su

Yapeng Su

California Institute of Technology - Division of Chemistry and Chemical Engineering

Xiang Lu

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

Guideng Li

California Institute of Technology - Division of Biology and Biological Engineering

Chunmei Liu

Institute for Systems Biology

Yan Kong

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Jihoon W. Lee

California Institute of Technology - Division of Chemistry and Chemical Engineering

Rachel Ng

California Institute of Technology - Division of Chemistry and Chemical Engineering

Stephanie Wong

California Institute of Technology - Division of Biology and Biological Engineering

Lidia Robert

University of California, Los Angeles (UCLA) - Department of Medicine

Charles Warden

City of Hope - Department of Molecular and Cellular Biology

Victoria Liu

California Institute of Technology - Division of Chemistry and Chemical Engineering

Jie Chen

Shanghai Jiao Tong University (SJTU) - MOE Key Laboratory of Systems Biomedicine (KLSB)

Zhuo Wang

Shanghai Jiao Tong University (SJTU) - MOE Key Laboratory of Systems Biomedicine (KLSB)

Yezi Yang

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

Hanjun Cheng

Institute for Systems Biology

Alphonsus H.C. Ng

Institute for Systems Biology

Guangrong Qin

Institute for Systems Biology

Songming Peng

California Institute of Technology - Division of Chemistry and Chemical Engineering

Min Xue

California Institute of Technology - Division of Chemistry and Chemical Engineering

Dazy Johnson

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

Yu Xu

Fudan University - Shanghai Cancer Center (FUSCC)

Jinhui Wang

City of Hope - Department of Molecular and Cellular Biology

Xiwei Wu

City of Hope - Department of Molecular and Cellular Biology

Ilya Shmulevich

Institute for Systems Biology

Qihui Shi

Shanghai Jiao Tong University (SJTU) - MOE Key Laboratory of Systems Biomedicine (KLSB)

Raphael Levine

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

Antoni Ribas

University of California, Los Angeles (UCLA) - Department of Medicine; University of California, Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center

David Baltimore

California Institute of Technology - Division of Biology and Biological Engineering

Jun Guo

Peking University - Key Laboratory of Carcinogenesis and Translational Research

James R. Heath

California Institute of Technology - Division of Chemistry and Chemical Engineering

Wei Wei

Institute for Systems Biology

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Abstract

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

Suggested Citation

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). CANCER-CELL-D-19-00753. Available at SSRN: https://ssrn.com/abstract=3439668 or http://dx.doi.org/10.2139/ssrn.3439668
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Yapeng Su

California Institute of Technology - Division of Chemistry and Chemical Engineering

1200 East California Boulevard
Pasadena, CA 91125
United States

Xiang Lu

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Guideng Li

California Institute of Technology - Division of Biology and Biological Engineering

Pasadena, CA 91125
United States

Chunmei Liu

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Yan Kong

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Jihoon W. Lee

California Institute of Technology - Division of Chemistry and Chemical Engineering

1200 East California Boulevard
Pasadena, CA 91125
United States

Rachel Ng

California Institute of Technology - Division of Chemistry and Chemical Engineering ( email )

1200 East California Boulevard
Pasadena, CA 91125
United States

Stephanie Wong

California Institute of Technology - Division of Biology and Biological Engineering

Pasadena, CA 91125
United States

Lidia Robert

University of California, Los Angeles (UCLA) - Department of Medicine

Los Angeles, CA
United States

Charles Warden

City of Hope - Department of Molecular and Cellular Biology

United States

Victoria Liu

California Institute of Technology - Division of Chemistry and Chemical Engineering

1200 East California Boulevard
Pasadena, CA 91125
United States

Jie Chen

Shanghai Jiao Tong University (SJTU) - MOE Key Laboratory of Systems Biomedicine (KLSB)

Shanghai, 200240
China

Zhuo Wang

Shanghai Jiao Tong University (SJTU) - MOE Key Laboratory of Systems Biomedicine (KLSB)

Shanghai, 200240
China

Yezi Yang

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Hanjun Cheng

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Alphonsus H.C. Ng

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Guangrong Qin

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Songming Peng

California Institute of Technology - Division of Chemistry and Chemical Engineering

1200 East California Boulevard
Pasadena, CA 91125
United States

Min Xue

California Institute of Technology - Division of Chemistry and Chemical Engineering

1200 East California Boulevard
Pasadena, CA 91125
United States

Dazy Johnson

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Yu Xu

Fudan University - Shanghai Cancer Center (FUSCC)

Shanghai, 200032
China

Jinhui Wang

City of Hope - Department of Molecular and Cellular Biology ( email )

United States

Xiwei Wu

City of Hope - Department of Molecular and Cellular Biology

United States

Ilya Shmulevich

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Qihui Shi

Shanghai Jiao Tong University (SJTU) - MOE Key Laboratory of Systems Biomedicine (KLSB)

Shanghai, 200240
China

Raphael Levine

University of California, Los Angeles (UCLA) - Department of Molecular and Medical Pharmacology (DMMP)

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Antoni Ribas

University of California, Los Angeles (UCLA) - Department of Medicine

Los Angeles, CA
United States

University of California, Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center

10833 Le Conte Avenue
Los Angeles, CA 90095-6939
United States

David Baltimore

California Institute of Technology - Division of Biology and Biological Engineering

Pasadena, CA 91125
United States

Jun Guo

Peking University - Key Laboratory of Carcinogenesis and Translational Research ( email )

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

James R. Heath

California Institute of Technology - Division of Chemistry and Chemical Engineering ( email )

1200 East California Boulevard
Pasadena, CA 91125
United States

Wei Wei (Contact Author)

Institute for Systems Biology ( email )

401 Terry Ave N.
Seattle, WA 98109
United States

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