Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance
Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance
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DOI：
10.1158/1078-0432.ccr-18-1205
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发表时间：
2018-11-01
影响因子：
11.5
通讯作者：
Shen, Lin
中科院分区：
文献类型：
--
作者：
Li, Yilin;Zhang, Xiaotian;Shen, Lin
目的：先前的人表皮生长因子受体-2（HER 2）衍生的耐药性研究是基于离体模型，其不能反映治疗期间HER 2的进化表达。为了研究HER 2的动态表达及其对染色体非整倍性赋予的治疗抗性的发展的贡献，在晚期胃癌（AGC）患者中共同检查了循环肿瘤细胞（CTC）上的HER 2表型和染色体8（Chr 8）非整倍性。共有115例AGC患者，其中56例组织病理学HER 2棘前瞻性入组接受一线HER 2靶向治疗加化疗的hHER 2（thorn）受试者和59例仅接受化疗的hHER 2（-）患者。结果：CTCs表面存在一种波动性的HER 2阳性表型（cHER 2 thorn），在治疗过程中的不同时间段出现cHER 2 thorn。在91.0%的hHER 2 thorn患者和76.2%的hHER 2（-）患者中获得cHER 2 thorn表型与hHER 2 thorn患者对曲妥珠单抗靶向治疗的耐药性和hHER 2（-）患者对单独化疗的耐药性相关。非整倍体Chr 8被证明参与收购的cHER 2刺表型，这提供了一个生长优势，HER 2刺CTCs对治疗的压力，导致发展的therapeutic resistance.Conclusions：与低阳性的常规组织病理学hHER 2检查常规进行一次，显着较高的阳性cHER 2刺CTCs观察。连续检查cHER 2显示出在肿瘤患者中真实的时间监测治疗抗性方面的独特优势。此外，染色体非整倍性对CTC上HER 2表达的表型进化的贡献可能有助于阐明产生治疗抗性的潜在机制。Clin Cancer（C）2018 AACR。
Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients.Experimental Design: A total of 115 AGC patients, including 56 of histopathologic HER2 thorn (hHER2 thorn) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2(-) patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy.Results: A fluctuated positive HER2 phenotype on CTCs (cHER2 thorn) was revealed, showing cHER2 thorn at different time intervals during treatment. Acquisition of the cHER2 thorn phenotype in 91.0% of hHER2 thorn and 76.2% hHER2(-) patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2 thorn patients and chemotherapy alone for hHER2(-) patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2 thorn phenotype, which provides a growth advantage to HER2 thorn CTCs against therapeutic pressure, leading to the development of therapeutic resistance.Conclusions: Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2 thorn on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. Clin Cancer (C) 2018 AACR.