Aberrant HER3 ligand heregulin-expressing head and neck squamous cell carcinoma is resistant to anti-EGFR antibody cetuximab, but not second-generation EGFR-TKI
Aberrant HER3 ligand heregulin-expressing head and neck squamous cell carcinoma is resistant to anti-EGFR antibody cetuximab, but not second-generation EGFR-TKI
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DOI：
10.1038/s41389-019-0164-9
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发表时间：
2019-09
期刊：
影响因子：
6.2
通讯作者：
K. Yonesaka;Kaoru Tanaka;M. Kitano;H. Kawakami;H. Hayashi;M. Takeda;K. Sakai;K. Nishio;K. Doi;K. Nakagawa
中科院分区：
文献类型：
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作者：
K. Yonesaka;Kaoru Tanaka;M. Kitano;H. Kawakami;H. Hayashi;M. Takeda;K. Sakai;K. Nishio;K. Doi;K. Nakagawa
抗表皮生长因子受体(EGFR)抗体西妥昔单抗是头颈部鳞状细胞癌(HNSCC)的标准治疗方法。然而，大多数HNSCC肿瘤对它具有耐药性，需要替代治疗。在这里，我们探讨了西妥昔单抗耐药的机制，并评估了其在HNSCC中的临床意义。对西妥昔单抗耐药的HNSCC FaDuCR细胞进行了无偏倚的全面转录组分析。用siRNA敲除致病耐药基因组，对细胞信号转导进行免疫学分析，并在体内外评价药物疗效。对28例切除的HNSCC肿瘤进行了致病基因的原位杂交(ISH)，并分析了其与西妥昔单抗疗效的关系。FaDuCR细胞对西妥昔单抗耐药，亲本FaDu细胞对西妥昔单抗敏感。尽管西妥昔单抗暴露，FaDuCR细胞表达的磷酸化Akt水平始终高于FaDu细胞。全面的转录组分析表明，与FaDu细胞相比，HER3-配体hereglin在FaDuCR细胞中上调。抑制HER3和Akt的磷酸化，并恢复西妥昔单抗的抗癌效果。相反，泛HER家族酪氨酸激酶抑制剂，如阿法替尼，降低了FaDuCR细胞中HER3和Akt的磷酸化，并抑制了FaDuCR肿瘤的生长。在28个HNSCC肿瘤样本中，有两个样本表现出与FaDuCR细胞类似的Hereglin异常表达，并且对西妥昔单抗耐药。在HNSCC中，hereglin介导的HER3-Akt激活导致对西妥昔单抗产生耐药性，但不对第二代EGFR-酪氨酸激酶抑制剂产生耐药性。HNSCC异常表达HNSCC的亚群可能对西妥昔单抗耐药。
The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is standard therapy for head and neck squamous cell carcinoma (HNSCC). However, most HNSCC tumors are resistant to it and require alternative treatments. Here, we explored the mechanism of cetuximab resistance and evaluated its clinical relevance in HNSCC. An unbiased comprehensive transcriptome analysis was performed on cetuximab-resistant HNSCC FaDuCR cells. The causative resistance genome was knocked down with siRNA, cell signaling was immunologically analyzed, and drug efficacy was evaluated in vitro and in vivo. The mRNA in situ hybridization (ISH) of the causative genome was performed using 28 excised HNSCC tumors and its relationship with cetuximab efficacy was analyzed. FaDuCR cells were resistant to cetuximab, whereas parental FaDu cells were susceptible to it. FaDuCR cells expressed consistently higher levels of phosphorylated Akt than FaDu cells despite cetuximab exposure. A comprehensive transcriptome analysis revealed that the HER3-ligand heregulin was upregulated in FaDuCR cells compared to FaDu cells. Heregulin knockdown in FaDuCR cells repressed HER3 and Akt phosphorylation and recovered cetuximab anticancer efficacy. In contrast, pan-HER family tyrosine kinase inhibitors such as afatinib decreased HER3 and Akt phosphorylation in FaDuCR cells and inhibited FaDuCR tumor growth. Two of the 28 HNSCC tumor samples presented aberrant heregulin expression comparable to that of FaDuCR cells and were resistant to cetuximab therapy. In HNSCC, heregulin-mediated HER3-Akt activation causes resistance to cetuximab but not to second-generation EGFR-tyrosine kinase inhibitors. Subpopulations with aberrant heregulin-expressing HNSCC might be resistant to cetuximab.