Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma

Dan Su; Dadong Zhang; Jiaoyue Jin; Lisha Ying; Miao Han; Kaiyan Chen; Bin Li; Junzhou Wu; Zhenghua Xie; Fanrong Zhang; Yihui Lin; Guoping Cheng; Jing Yu Li; Minran Huang; Jinchao Wang; Kailai Wang; Jianjun Zhang; Fugen Li; Lei Xiong; Andrew Futreal; Weimin Mao

doi:10.1038/s41467-019-12846-7

Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma

Dan Su, Dadong Zhang, Jiaoyue Jin, Lisha Ying, Miao Han, Kaiyan Chen, Bin Li, Junzhou Wu, Zhenghua Xie, Fanrong Zhang, Yihui Lin, Guoping Cheng, Jing Yu Li, Minran Huang, Jinchao Wang, Kailai Wang, Jianjun Zhang, Fugen Li, Lei Xiong, Andrew FutrealWeimin Mao

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.

Original language	English (US)
Article number	5076
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12846-7
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Su, D., Zhang, D., Jin, J., Ying, L., Han, M., Chen, K., Li, B., Wu, J., Xie, Z., Zhang, F., Lin, Y., Cheng, G., Li, J. Y., Huang, M., Wang, J., Wang, K., Zhang, J., Li, F., Xiong, L., ... Mao, W. (2019). Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma. Nature communications, 10(1), Article 5076. https://doi.org/10.1038/s41467-019-12846-7

Su, D, Zhang, D, Jin, J, Ying, L, Han, M, Chen, K, Li, B, Wu, J, Xie, Z, Zhang, F, Lin, Y, Cheng, G, Li, JY, Huang, M, Wang, J, Wang, K, Zhang, J, Li, F, Xiong, L, Futreal, A & Mao, W 2019, 'Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma', Nature communications, vol. 10, no. 1, 5076. https://doi.org/10.1038/s41467-019-12846-7

@article{a94170dd985b4637994eb48734835333,

title = "Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma",

abstract = "Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.",

author = "Dan Su and Dadong Zhang and Jiaoyue Jin and Lisha Ying and Miao Han and Kaiyan Chen and Bin Li and Junzhou Wu and Zhenghua Xie and Fanrong Zhang and Yihui Lin and Guoping Cheng and Li, {Jing Yu} and Minran Huang and Jinchao Wang and Kailai Wang and Jianjun Zhang and Fugen Li and Lei Xiong and Andrew Futreal and Weimin Mao",

note = "Funding Information: This study was partially supported by the National Health Commission Scientific Research Fund-Zhejiang Medical and Health Major Science and Technology Program (WKJ-ZJ-1902 to D.S.), the National Natural Science Foundation of China (Grant No. 81472203 and 81972917 to D.S.) and the High-Level Creative and Innovative Health Talent Program of Zhejiang Province (to D.S.). We thank all the patients and their families for their support of this study. We also thank Nishihira Tetsuro for his authorization of our use of ESCC cell lines, including TE-1, TE-6, TE-8, TE-11, TE-14, and TE-15. We thank Hua Dong, Changgen Ding, Yinming Jiao, Zisong Zhou, Xiaoya Xu, and Zishuo Chen for their assistance in conducting the experiments in this study. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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day = "1",

doi = "10.1038/s41467-019-12846-7",

language = "English (US)",

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T1 - Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma

AU - Su, Dan

AU - Zhang, Dadong

AU - Jin, Jiaoyue

AU - Ying, Lisha

AU - Han, Miao

AU - Chen, Kaiyan

AU - Li, Bin

AU - Wu, Junzhou

AU - Xie, Zhenghua

AU - Zhang, Fanrong

AU - Lin, Yihui

AU - Cheng, Guoping

AU - Li, Jing Yu

AU - Huang, Minran

AU - Wang, Jinchao

AU - Wang, Kailai

AU - Zhang, Jianjun

AU - Li, Fugen

AU - Xiong, Lei

AU - Futreal, Andrew

AU - Mao, Weimin

N1 - Funding Information: This study was partially supported by the National Health Commission Scientific Research Fund-Zhejiang Medical and Health Major Science and Technology Program (WKJ-ZJ-1902 to D.S.), the National Natural Science Foundation of China (Grant No. 81472203 and 81972917 to D.S.) and the High-Level Creative and Innovative Health Talent Program of Zhejiang Province (to D.S.). We thank all the patients and their families for their support of this study. We also thank Nishihira Tetsuro for his authorization of our use of ESCC cell lines, including TE-1, TE-6, TE-8, TE-11, TE-14, and TE-15. We thank Hua Dong, Changgen Ding, Yinming Jiao, Zisong Zhou, Xiaoya Xu, and Zishuo Chen for their assistance in conducting the experiments in this study. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.

AB - Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.

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JO - Nature communications

JF - Nature communications

IS - 1

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ER -

Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma

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