Department of Medicine & Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143-1387, USA.
Clin Cancer Res. 2010 Mar 1;16(5):1373-83. doi: 10.1158/1078-0432.CCR-09-1218. Epub 2010 Feb 23.
The human epidermal growth family (HER) of tyrosine kinase receptors underlies the pathogenesis of many types of human cancer. The oncogenic functions of three of the HER proteins can be unleashed through amplification, overexpression, or mutational activation. This has formed the basis for the development of clinically active targeted therapies. However, the third member HER3 is catalytically inactive, not found to be mutated or amplified in cancers, and its role and functions have remained shrouded in mystery. Recent evidence derived primarily from experimental models now seems to implicate HER3 in the pathogenesis of several types of cancer. Furthermore, the failure to recognize the central role of HER3 seems to underlie resistance to epidermal growth factor receptor (EGFR)- or HER2-targeted therapies in some cancers. Structural and biochemical studies have now greatly enhanced our understanding of signaling in the HER family and revealed the previously unrecognized activating functions embodied in the catalytically impaired kinase domain of HER3. This renewed interest and mechanistic basis has fueled the development of new classes of HER3-targeting agents for cancer therapy. However, identifying HER3-dependent tumors presents a formidable challenge and the success of HER3-targeting approaches depends entirely on the development and power of predictive tools.
人类表皮生长因子家族（HER）的酪氨酸激酶受体是许多类型人类癌症发病机制的基础。三种 HER 蛋白的致癌功能可以通过扩增、过表达或突变激活来释放。这为开发临床有效的靶向治疗奠定了基础。然而，HER3 的第三个成员是无催化活性的，在癌症中未发现突变或扩增，其作用和功能仍然是个谜。最近主要来自实验模型的证据似乎表明 HER3 在几种类型的癌症发病机制中起作用。此外，未能认识到 HER3 的核心作用似乎是某些癌症中表皮生长因子受体（EGFR）或 HER2 靶向治疗耐药的基础。结构和生化研究极大地提高了我们对 HER 家族信号转导的理解，并揭示了 HER3 中催化受损激酶结构域所具有的以前未被认识到的激活功能。这种新的兴趣和机制基础推动了开发用于癌症治疗的新型 HER3 靶向药物。然而，确定 HER3 依赖性肿瘤是一个艰巨的挑战，HER3 靶向方法的成功完全取决于预测工具的开发和实力。
