Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer
Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer
复制标题
人类乳腺癌 HER2 靶向治疗中新型 HER2 激酶结构域突变的双重特征
DOI：
10.1158/1078-0432.ccr-15-3036
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发表时间：
2016-10-01
影响因子：
11.5
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Zuo, Wen-Jia;Jiang, Yi-Zhou;Shao, Zhi-Ming
目的：人表皮生长因子受体2（HER 2）酪氨酸激酶结构域的体细胞突变可能是HER 2激活的替代机制，并可能影响对HER 2靶向治疗的敏感性。我们的目的是研究乳腺癌中新的HER 2突变的患病率、临床病理学特征和功能相关性。实验设计：我们对1,248例原发性肿瘤和18例配对转移性肿瘤样本中的HER 2基因的所有外显子进行了桑格测序。新的HER 2突变的功能特征。结果：1248例患者中，HER 2基因体细胞突变率为2.24%（28/1,248）。在7种新的HER 2突变中，L768 S和V773 L仅在HER 2阴性肿瘤中检测到，而K753 E在HER 2阳性疾病中发现。L768 S和V773 L突变表现出酪氨酸激酶特异性活性的显着增加，并强烈增加各种细胞系中信号蛋白的磷酸化。异种移植实验表明，携带L768 S和V773 L突变的NIH 3 T3细胞显示出更快的生长。携带K753 E突变的MCF 10A、BT 474和MDA-MB-231细胞对拉帕替尼耐药，但可被来那替尼抑制。最后，比较18对原发性和转移性病灶中的HER 2突变，发现耐药HER 2突变（K753 E和L755 S）在转移性病灶中富集。结论：具有激活突变的HER 2阴性乳腺癌可以从HER 2靶向治疗中获益。同时，HER 2激酶结构域的突变可能是HER 2靶向治疗耐药的关键机制，不可逆酪氨酸激酶抑制剂（如来那替尼）可能提供替代治疗选择。Clin Cancer Res; 22（19）; 4859-69.©2016 AACR版权所有
Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer. Experimental Design: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized. Results: The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase–specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions. Conclusions: HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859–69. ©2016 AACR.