Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block.
Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block.
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DOI：
10.2174/187152211795495643
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
Ghosh PM
中科院分区：
文献类型：
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作者：
Jathal MK;Chen L;Mudryj M;Ghosh PM
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。 PCa 发病时具有雄激素依赖性，虽然可以通过手术或药物阻断 AR（雄激素消融）暂时停止，但该疾病最终会复发，成为一种侵袭性、致命的去势抵抗性前列腺癌 (CRPC)。 FDA 批准的化疗药物多西紫杉醇和癌症疫苗 Provenge 等治疗方法分别可将生存期延长 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 ErbB 家族（EGFR/ErbB1、ErbB2/HER2/neu、ErbB3/HER3 和 ErbB4/HER4）长期以来一直与 PCa 的发生和进展有关，但 ErbB1 和 ErbB2（原型家族成员）的抑制剂在 PCa 临床试验中表现不佳。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。人们正在努力了解 ErbB3 介导的去势抵抗分子机制，并寻找通过合理的药物设计抑制 ErbB3 活性的新方法。阻止配体与 ErbB3 结合的抗体疗法似乎很有前途，抑制配体诱导的 ErbB3 磷酸化的完全人源化抗体目前正处于早期开发阶段。小分子酪氨酸激酶抑制剂也得到了大力研究，基于 siRNA 的方法和联合治疗策略（同时抑制 ErbB3 及其信号伙伴或下游效应子）的主要目的是破坏 ErbB3 介导的信号转导的弹性。本综述总结了现有文献，并强调了 ErbB3 作为前列腺癌临床治疗靶点的重要性。
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.