Research Papers:

Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification

Yongxin Ren, Jianming Zheng, Shiming Fan, Linfang Wang, Min Cheng, Dongxia Shi, Wei Zhang, Renxiang Tang, Ying Yu, Longxian Jiao, Jun Ni, Haibin Yang, Huaqing Cai, Fang Yin, Yunxin Chen, Feng Zhou, Weihan Zhang, Weiguo Qing and Weiguo Su _

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Oncotarget. 2017; 8:50832-50844. https://doi.org/10.18632/oncotarget.17243

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Yongxin Ren1,*, Jianming Zheng2,*, Shiming Fan1,*, Linfang Wang1, Min Cheng1, Dongxia Shi1, Wei Zhang1, Renxiang Tang1, Ying Yu1, Longxian Jiao1, Jun Ni1, Haibin Yang3, Huaqing Cai3, Fang Yin1, Yunxin Chen1, Feng Zhou1, Weihan Zhang3, Weiguo Qing1 and Weiguo Su3

1Department of Oncology Research, Hutchison MediPharma Limited, Shanghai, China

2Department of Pathology, Changhai Hospital, the Second Military Medical University, Shanghai, China

3Department of Chemistry, Hutchison MediPharma Limited, Shanghai, China

*These authors are contributed equally to this work

Correspondence to:

Yongxin Ren, email: [email protected]

Weiguo Su, email: [email protected]

Keywords: esophageal cancer, patient derived xenograft models, EGFR targeted therapy, theliatinib

Received: December 01, 2016     Accepted: March 27, 2017     Published: April 19, 2017


Targeted therapy is not yet approved for esophageal cancer (EC). In this study, we first evaluated EGFR gene and protein expression in 70 Chinese EC patient tumor samples collected during surgery. We then established 23 patient-derived EC xenograft (PDECX) models and assessed the efficacy of theliatinib, a potent and highly selective EGFR inhibitor currently in Phase I clinical study, in 9 PDECX models exhibiting various EGFR expression levels. Immunohistochemical analysis showed that 50 patient tumor samples (71.4%) had high EGFR expression. Quantitative PCR showed that eight tumors (11.6%) had EGFR gene copy number gain, and fluorescence in situ hybridization (FISH) revealed that four tumors had EGFR gene amplification. These results suggest that EGFR protein may be overexpressed in many EC tumors without gene amplification. Also detected were rare hot-spot mutations in EGFR and PIK3CA, whereas no mutations were found in K-Ras or B-Raf. Theliatinib exhibited strong antitumor activity in PDECX models with high EGFR expression, including remarkable tumor regression in two PDECX models with both EGFR gene amplification and protein overexpression. However, the efficacy of theliatinib was diminished in models with PI3KCA mutations or FGFR1 overexpression in addition to high EGFR expression. This study demonstrates that theliatinib could potentially benefit EC patients with high EGFR protein expression without mutations or aberrant activities of associated factors, such as PI3KCA or FGFR1.

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