Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models

Journal of Translational Medicine

Di Ge³  Yingyong Hou²  Qunsheng Ji¹  Deming He²  Xiaolu Yin¹  Liang Xie¹  Yunshan Tan²  Chen Xu²  Yalan Liu²  Jun Hou²  Shaohua Lu²  Songtao Xu³  Paul R Gavine¹  Guanshan Zhu¹  Xinying Su¹  Li Zheng¹  Jing Lv¹  Ruheng Zhen³  Jingchuan Zhang¹  Xianhua Wu³ 

[1] Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China;Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China;Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China

关键词: Xenograft model;    PIK3CA mutation;    Herceptin;    HER-2;    Esophageal carcinoma;   

Others  :  1205901
DOI  :  10.1186/1479-5876-10-180

 received in 2012-05-03, accepted in 2012-08-28,  发布年份 2012

【 摘 要 】

Background

Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models.

Methods

PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC) tissues into immunodeficient (SCID/nude) mice. HER-2 gene copy number (GCN) and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group). Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation.

Results

None of the PDECX models (or their corresponding patient’s ESCC tissues) harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+) in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+). A second HER-2 positive (IHC 2+) model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model.

Conclusions

This study demonstrates Trastuzumab-induced tumor regressions in HER-2 positive tumors, and highlights PIK3CA mutation as a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models.

【 授权许可】

   
2012 Wu et al.; licensee BioMed Central Ltd.

【 图 表 】

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