Oncogenic HER2 fusions in gastric cancer

Journal of Translational Medicine

Qunsheng Ji¹  Jiafu Ji³  Xiaolin Zhang⁴  Xiaolu Yin⁴  Jingchuan Zhang⁴  Qingqing Ye⁴  Jia Wang⁴  Guanshan Zhu⁴  Ziliang Qian⁴  Hao Chen²  Liang Xie⁴  Lu Han⁴  Haihua Fu⁴  Tianwei Zhang⁴  Xinying Su⁴  Jiangang Fu⁴  Lianhai Zhang³  Zhengwei Dong⁴  Hua Dong⁴  Lili Tang⁴  De-Hua Yu⁴ 

[1] Current mailing address: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao, China (Shanghai) Pilot Free Trade Zone, Shanghai 200131, China;Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, China;Innovation Center China, Asia & Emerging Market iMed, AstraZeneca Innovation Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China

关键词: Lapatinib;    Trastuzumab;    Gastric cancer;    Fusion-gene;    HER2;   

Others  :  1207758
DOI  :  10.1186/s12967-015-0476-2

 received in 2014-12-29, accepted in 2015-03-25,  发布年份 2015

【 摘 要 】

Background

Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood.

Methods

We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants.

Results

We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab.

Conclusions

Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options.

【 授权许可】

   
2015 Yu et al.; licensee BioMed Central.

【 图 表 】

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