Jathal Maitreyee K, Chen Liqun, Mudryj Maria, Ghosh Paramita M
Department of Urology, University of California Davis, CA. USA.
Immunol Endocr Metab Agents Med Chem. 2011 Jun;11(2):131-149. doi: 10.2174/187152211795495643.
Most prostate cancers (PCa) are critically reliant on functional androgen receptor (AR) signaling. At its onset, PCa is androgen-dependent and although temporarily halted by surgically or pharmacologically blocking the AR (androgen ablation), the disease ultimately recurs as an aggressive, fatal castration resistant prostate cancer (CRPC). FDA-approved treatments like docetaxel, a chemotherapeutic agent, and Provenge, a cancer vaccine, extend survival by a scant 3 and 4 months, respectively. It is clear that more effective drugs targeting CRPC are urgently needed. The ErbB family (EGFR/ErbB1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) of receptor tyrosine kinases (RTKs) have long been implicated in PCa initiation and progression, but inhibitors of ErbB1 and ErbB2 (prototypic family members) fared poorly in PCa clinical trials. Recent research suggests that another family member ErbB3 abets emergence of the castration-resistant phenotype. Considerable efforts are being directed towards understanding ErbB3-mediated molecular mechanisms of castration resistance and searching for novel ways of inhibiting ErbB3 activity via rational drug design. Antibody-based therapy that prevents ligand binding to ErbB3 appears promising and fully-humanized antibodies that inhibit ligand-induced phosphorylation of ErbB3 are currently in early development. Small molecule tyrosine kinase inhibitors are also being vigorously pursued, as are siRNA-based approaches and combination treatment strategies- the simultaneous suppression of ErbB3 and its signaling partners or downstream effectors - with the primary purpose of undermining the resiliency of ErbB3-mediated signal transduction. This review summarizes the existing literature and reinforces the importance of ErbB3 as a therapeutic target in the clinical management of prostate cancer.
大多数前列腺癌（PCa）严重依赖功能性雄激素受体（AR）信号传导。在发病初期，PCa是雄激素依赖性的，尽管通过手术或药物阻断AR（雄激素去除）可暂时阻止疾病进展，但该疾病最终会复发为侵袭性、致命的去势抵抗性前列腺癌（CRPC）。美国食品药品监督管理局（FDA）批准的治疗方法，如化疗药物多西他赛和癌症疫苗普罗文奇，分别仅将生存期延长了3个月和4个月。显然，迫切需要更有效的针对CRPC的药物。受体酪氨酸激酶（RTK）的表皮生长因子受体（ErbB）家族（EGFR/ErbB1、ErbB2/HER2/neu、ErbB3/HER3和ErbB4/HER4）长期以来一直被认为与PCa的发生和发展有关，但ErbB1和ErbB2（该家族的典型成员）的抑制剂在PCa临床试验中效果不佳。最近的研究表明，另一个家族成员ErbB3促进了去势抵抗表型的出现。目前正在投入大量精力来了解ErbB3介导的去势抵抗分子机制，并通过合理的药物设计寻找抑制ErbB3活性的新方法。基于抗体的疗法可防止配体与ErbB3结合，似乎很有前景，目前抑制配体诱导的ErbB3磷酸化的全人源抗体正处于早期开发阶段。小分子酪氨酸激酶抑制剂也在大力研发中，基于RNA干扰（siRNA）的方法和联合治疗策略（同时抑制ErbB3及其信号传导伙伴或下游效应器）也在积极探索中，其主要目的是破坏ErbB3介导的信号转导的弹性。这篇综述总结了现有文献，并强调了ErbB3作为前列腺癌临床管理中治疗靶点的重要性。
