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 and Weimin Mao ()
Additional contact information
Dan Su: Chinese Academy of Sciences
Dadong Zhang: 3D Medicines Inc.
Jiaoyue Jin: Cancer Hospital of the University of Chinese Academy of Sciences
Lisha Ying: Chinese Academy of Sciences
Miao Han: 3D Medicines Inc.
Kaiyan Chen: Cancer Hospital of the University of Chinese Academy of Sciences
Bin Li: 3D Medicines Inc.
Junzhou Wu: Chinese Academy of Sciences
Zhenghua Xie: 3D Medicines Inc.
Fanrong Zhang: Cancer Hospital of the University of Chinese Academy of Sciences
Yihui Lin: 3D Medicines Inc.
Guoping Cheng: Cancer Hospital of the University of Chinese Academy of Sciences
Jing-Yu Li: 3D Medicines Inc.
Minran Huang: Chinese Academy of Sciences
Jinchao Wang: 3D Medicines Inc.
Kailai Wang: Chinese Academy of Sciences
Jianjun Zhang: University of Texas MD Anderson Cancer Center
Fugen Li: 3D Medicines Inc.
Lei Xiong: 3D Medicines Inc.
Andrew Futreal: University of Texas MD Anderson Cancer Center
Weimin Mao: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12846-7

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