中国学者发现影响乳腺癌HER2靶向疗法效果的HER2激酶结构区新突变双重特征

　　2016年10月1日，美国癌症研究协会官方期刊《临床癌症研究》正式发表复旦大学附属肿瘤医院、上海医学院、生物医学研究院左文佳、江一舟、王玉洁、徐晓恩、胡欣、柳光宇、吴炅、狄根红、余科达、邵志敏等学者的研究报告，发现影响乳腺癌HER2靶向疗法效果的HER2激酶结构区新突变双重特征。

　　体细胞HER2酪氨酸激酶结构区突变可能是一种HER2活化替代机制，并可影响对HER2靶向疗法的敏感性。该研究探讨了乳腺癌HER2新突变的发生率、临床病理特征、功能相关性。

　　该研究对1248例原发肿瘤和18例配对转移标本进行HER2基因所有外显子的桑格测序，分析HER2新突变的功能特征。

　　结果发现，体细胞HER2总突变率为2.24% （28/1248）。在7个HER2新突变中，L768S和V773L仅见于HER2阴性肿瘤，而K753E见于HER2阳性病灶。L768S和V773L突变表现出酪氨酸激酶特异活性显著增加，并显著增加各细胞系信号转导蛋白质磷酸化。异种移植实验表明，L768S和V773L突变的NIH3T3细胞生长较快。K753E突变的MCF10A、BT474和MDA-MB-231细胞对拉帕替尼耐药，但可被奈拉替尼（来那替尼）抑制。最后，通过比较18对原发和转移病灶的HER2突变，发现耐药HER2突变（K753E和L755S）集中于转移病灶。

　　因此，发生突变的HER2阴性乳腺癌可获益于HER2靶向疗法。同时，HER2激酶结构区突变可能是HER2靶向疗法耐药的一个重要机制，不可逆酪氨酸激酶抑制剂如奈拉替尼（来那替尼）可能提供替代治疗选择。

Clin Cancer Res. 2016 Oct 1;22(19):4859-69.

Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer.

Zuo WJ, Jiang YZ, Wang YJ, Xu XE, Hu X, Liu GY, Wu J, Di GH, Yu KD, Shao ZM.

Fudan University Shanghai Cancer Center, Shanghai, PR China; Shanghai Medical College, Fudan University, Shanghai, PR China; Institute of Biomedical Sciences, Fudan University, Shanghai, PR China.

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.

PMID: 27697991

DOI: 10.1158/1078-0432.CCR-15-3036