Activating HER2 mutations in HER2 gene amplification negative breast cancer.
Activating HER2 mutations in HER2 gene amplification negative breast cancer.
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DOI：
10.1158/2159-8290.cd-12-0349
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发表时间：
2013-02
期刊：
影响因子：
28.2
通讯作者：
Ellis MJ
中科院分区：
文献类型：
--
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
来自8个乳腺癌基因组测序项目的数据确定了25名在缺乏HER 2基因扩增的癌症中具有HER 2体细胞突变的患者。为了确定这些突变的表型，我们使用体外激酶测定、蛋白质结构分析、细胞培养和异种移植实验对13种HER 2突变进行功能表征。这些突变中有7个是激活突变，包括G309 A、D 769 H、D 769 Y、V777 L、P780 ins、V842 I和R896 C。与EGFR外显子19框内缺失同源的HER 2框内缺失755-759具有EGFR或HER 3磷酸化增加的新形态表型。L755 S产生拉帕替尼抗性，但在我们的实验系统中不是激活突变。所有这些突变均对不可逆激酶抑制剂来那替尼敏感。这些发现表明，HER 2体细胞突变是激活乳腺癌中HER 2的替代机制，并且它们验证了HER 2体细胞突变作为乳腺癌治疗的药物靶标。
Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.