Deng Xiaohong, Zheng Xuxu, Yang Huanming, Moreira José Manuel Afonso, Brünner Nils, Christensen Henrik
Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, China; Section of Molecular Disease Biology, and Sino-Danish Breast Cancer Research Centre, Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Beijing Genomics Institute and Sino-Danish Breast Cancer Research Centre, Shenzhen, China.
Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, China.
PLoS One. 2014 Sep 5;9(9):e106448. doi: 10.1371/journal.pone.0106448. eCollection 2014.
Overexpression of human epidermal growth factor receptor 2 (HER2) is associated with tumor aggressiveness and poor prognosis in breast cancer. With the availability of therapeutic antibodies against HER2, great strides have been made in the clinical management of HER2 overexpressing breast cancer. However, de novo and acquired resistance to these antibodies presents a serious limitation to successful HER2 targeting treatment. The identification of novel epitopes of HER2 that can be used for functional/region-specific blockade could represent a central step in the development of new clinically relevant anti-HER2 antibodies. In the present study, we present a novel computational approach as an auxiliary tool for identification of novel HER2 epitopes. We hypothesized that the structurally and linearly evolutionarily conserved motifs of the extracellular domain of HER2 (ECD HER2) contain potential druggable epitopes/targets. We employed the PROSITE Scan to detect structurally conserved motifs and PRINTS to search for linearly conserved motifs of ECD HER2. We found that the epitopes recognized by trastuzumab and pertuzumab are located in the predicted conserved motifs of ECD HER2, supporting our initial hypothesis. Considering that structurally and linearly conserved motifs can provide functional specific configurations, we propose that by comparing the two types of conserved motifs, additional druggable epitopes/targets in the ECD HER2 protein can be identified, which can be further modified for potential therapeutic application. Thus, this novel computational process for predicting or searching for potential epitopes or key target sites may contribute to epitope-based vaccine and function-selected drug design, especially when x-ray crystal structure protein data is not available.
人表皮生长因子受体2（HER2）的过表达与乳腺癌的肿瘤侵袭性和不良预后相关。随着抗HER2治疗性抗体的出现，HER2过表达乳腺癌的临床管理取得了巨大进展。然而，对这些抗体的原发性和获得性耐药对HER2靶向治疗的成功构成了严重限制。鉴定可用于功能性/区域特异性阻断的HER2新表位可能是开发新的临床相关抗HER2抗体的关键步骤。在本研究中，我们提出了一种新的计算方法作为鉴定HER2新表位的辅助工具。我们假设HER2细胞外结构域（ECD HER2）的结构和线性进化保守基序包含潜在的可药物化表位/靶点。我们使用PROSITE Scan检测结构保守基序，并使用PRINTS搜索ECD HER2的线性保守基序。我们发现曲妥珠单抗和帕妥珠单抗识别的表位位于ECD HER2的预测保守基序中，支持了我们最初的假设。考虑到结构和线性保守基序可以提供功能特异性构型，我们建议通过比较这两种保守基序，可以鉴定ECD HER2蛋白中额外的可药物化表位/靶点，这些表位/靶点可以进一步修饰用于潜在的治疗应用。因此，这种预测或搜索潜在表位或关键靶位点的新计算方法可能有助于基于表位的疫苗和功能选择药物设计，特别是在缺乏X射线晶体结构蛋白数据的情况下。
