Suárez Narjara González, Báez Gretchen Bergado, Rodríguez Mabel Cruz, Pérez Amelia Gutiérrez, García Lisset Chao, Hernández Fernández Diana Rosa, Pous Judith Raymond, Ramírez Belinda Sánchez
Tumor Immunology Direction, Molecular Immunology Institute, Center of Molecular Immunology, Havana 11600, Cuba.
System Biology Direction, Molecular Immunology Institute, Center of Molecular Immunology, Havana 11600, Cuba.
Oncotarget. 2017 Aug 3;8(47):82872-82884. doi: 10.18632/oncotarget.19958. eCollection 2017 Oct 10.
The human epidermal growth factor receptor (HER1) and its partner HER2 are extensively described oncogenes and validated targets for cancer therapy. However, the effectiveness of monospecific therapies targeting these receptors is hampered by resistance emergence, which is frequently associated with the upregulation of other members of HER family. Combined therapies using monoclonal antibodies or tyrosine kinase inhibitors have been suggested as a promising strategy to circumvent this resistance mechanism. We propose an alternative approach based on simultaneous inactivation of HER1 and HER2 by multi-epitope blockade with specific polyclonal antibodies induced by vaccination. Elicited antibodies impaired both receptors activation and induced their degradation, which caused the inhibition of down-signaling cascades. This effect was translated into cell cycle arrest and apoptosis induction of human tumor cells. Elicited antibodies were able to reduce the viability of a panel of human tumor lines with differential expression levels of HER1 and HER2. The most significant effects were obtained in the tumor lines with lower expression levels of both receptors. These new insights would contribute to the rational design of HER receptors targeting multivalent vaccines, as an encouraging approach for the treatment of cancer patients.
人表皮生长因子受体（HER1）及其伴侣HER2是被广泛描述的癌基因，也是经过验证的癌症治疗靶点。然而，靶向这些受体的单特异性疗法的有效性受到耐药性出现的阻碍，而耐药性的出现通常与HER家族其他成员的上调有关。使用单克隆抗体或酪氨酸激酶抑制剂的联合疗法已被认为是一种有前景的策略，以规避这种耐药机制。我们提出了一种基于通过接种疫苗诱导的特异性多克隆抗体进行多表位阻断同时使HER1和HER2失活的替代方法。产生的抗体损害了两种受体的激活并诱导其降解，从而导致下游信号级联反应的抑制。这种效应转化为人类肿瘤细胞的细胞周期停滞和凋亡诱导。产生的抗体能够降低一组HER1和HER2表达水平不同的人类肿瘤细胞系的活力。在两种受体表达水平较低的肿瘤细胞系中获得了最显著的效果。这些新见解将有助于合理设计靶向HER受体的多价疫苗，作为治疗癌症患者的一种令人鼓舞的方法。
