EGFR家族受体的分子结构与药物作用机制

Structural basis for EGFR transmembrane signaling and its implications in therapeutic development

表皮生长因子受体(EGFR)及其同源蛋白HER2,HER3,HER4是调控细胞生长与分化的重要酪氨酸激酶受体.这些受体的突变或过表达将会引起激酶活性的失调,并导致包括肺癌与乳腺癌在内的各种癌症.因此,这些受体是治疗癌症的重要药物靶点.虽然目前对于EGFR激酶突变所引起的激酶活性失调及其致癌机制已有较深入的研究,但对于由EGFR或HER2过表达所引发的跨膜信号变化,相应的分子结构,以及由此导致的癌症发生与耐药性产生的分子机制则均不甚明了,在临床上也缺乏有效的靶向性药物或治疗窗口.本文将对EGFR家族受体的分子结构、跨膜信号传导机制,以及EGFR靶向药物的研究进行回顾和展望.

Epidermal growth factor receptor（EGFR） and its homologs（HER2, HER3, and HER4） belong to receptor tyrosine kinase（RTK）superfamily. They regulate important cellular functions, including cell growth, differentiation, and proliferation. Dysregulation of these receptor transmembrane signaling, either by mutation or by overexpression, leads to oncogenesis. Therefore, they are validated therapeutic targets in the treatment of various cancers, such as lung and breast cancers. Although significant progress has been achieved in understanding the basis for oncogenesis associated with EGFR kinase mutation, less is known about how the transmembrane signaling is dysregulated by EGFR or HER2 overexpression, and how EGFR or HER2 overexpression contributes to oncogenesis and drug resistance. Herein, we review the progress in the structural studies of these receptors＇ transmembrane signaling and the development of their targeted therapeutics.