Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of General Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Clin Cancer Res. 2018 Oct 15;24(20):5112-5122. doi: 10.1158/1078-0432.CCR-18-0991. Epub 2018 Jul 2.
The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the mutations in a high-throughput manner. We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous mutations using the mixed-all-nominated-in-one (MANO) method. G776V, G778_S779insG, and L841V were newly revealed to be activating mutations. Although afatinib, neratinib, and osimertinib were shown to be effective against most of the mutations, only osimertinib demonstrated good efficacy against L755P and L755S mutations, the most common mutations in breast cancer. In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent mutation in lung cancer. We surveyed the prevalence of concurrent mutation with gene amplification and found that approximately 30% of ERBB2-amplified urothelial carcinomas simultaneously carried mutations, altering their sensitivity to trastuzumab, an mAb against ERBB2. Furthermore, the MANO method was applied to evaluate the functional significance of 17 compound mutations within reported in the COSMIC database, revealing that compound mutations involving L755S were sensitive to osimertinib but insensitive to afatinib and neratinib. Several mutations showed varying sensitivities to ERBB2-targeted inhibitors. Our comprehensive assessment of mutations offers a fundamental database to help customize therapy for ERBB2-driven cancers.We identified several mutations as activating mutations related to tumorigenesis. In addition, our comprehensive evaluation revealed that several mutations showed varying sensitivities to ERBB2-targeted inhibitors, and thus, the functional significance of each variant should be interpreted precisely to design the best treatment for each patient. .
下一代测序技术的出现使得能够在各种癌症中鉴定出 Erb-B2 受体酪氨酸激酶 2（ERBB2）的几种激活突变。然而，不频繁突变的意义尚未得到充分研究。在此，我们以高通量的方式全面评估了这些突变的功能意义。我们使用混合提名法（MANO）方法评估了 55 种非同义 突变的转化活性和药物敏感性。G776V、G778_S779insG 和 L841V 被新揭示为激活突变。尽管阿法替尼、奈拉替尼和奥希替尼对大多数 突变有效，但只有奥希替尼对乳腺癌中最常见的 L755P 和 L755S 突变显示出良好的疗效。相比之下，阿法替尼和奈拉替尼被预测对肺癌中最常见的 突变 A775_776insYVMA 突变的疗效优于其他抑制剂。我们调查了 突变与基因扩增的共存情况，发现约 30%的 ERBB2 扩增型膀胱癌同时携带 突变，改变了它们对曲妥珠单抗（一种针对 ERBB2 的 mAb）的敏感性。此外，我们还应用 MANO 方法评估了 COSMIC 数据库中报道的 17 种复合突变的功能意义，发现涉及 L755S 的复合突变对奥希替尼敏感，但对阿法替尼和奈拉替尼不敏感。几种 突变对 ERBB2 靶向抑制剂的敏感性不同。我们对 突变的全面评估为帮助定制 ERBB2 驱动的癌症治疗提供了基本数据库。我们鉴定了几种与肿瘤发生相关的 突变作为激活突变。此外，我们的全面评估显示，几种 突变对 ERBB2 靶向抑制剂的敏感性不同，因此，应该准确解释每个变体的功能意义，以设计每位患者的最佳治疗方案。
