The Institute for Cancer Research, London, UK.
The Royal Marsden NHS Foundation Trust, London, UK.
Nat Rev Clin Oncol. 2018 Nov;15(11):663-675. doi: 10.1038/s41571-018-0085-0.
Androgen receptor (AR) splice variants (AR-Vs) have been implicated in the development and progression of metastatic prostate cancer. AR-Vs are truncated isoforms of the AR, a subset of which lack a ligand-binding domain and remain constitutively active in the absence of circulating androgens, thus promoting cancer cell proliferation. Consequently, AR-Vs have been proposed to contribute not only to resistance to anti-androgen therapies but also to resistance to radiotherapy in patients receiving combination therapy by promoting DNA repair. AR-Vs, such as AR-V7, have been associated with unfavourable clinical outcomes in patients; however, attempts to specifically inhibit or prevent the formation of AR-Vs have, to date, been unsuccessful. Thus, novel therapeutic strategies are desperately needed to address the oncogenic effects of AR-Vs, which can drive lethal forms of prostate cancer. Disruption of alternative splicing through modulation of the spliceosome is one such potential therapeutic avenue; however, our understanding of the biology of the spliceosome and how it contributes to prostate cancer remains incomplete, as reflected in the dearth of spliceosome-targeted therapeutic agents. In this Review, the authors outline the current understanding of the role of the spliceosome in the progression of prostate cancer and explore the therapeutic utility of manipulating alternative splicing to improve patient care.
雄激素受体 (AR) 剪接变异体 (AR-Vs) 被认为与转移性前列腺癌的发生和发展有关。AR-Vs 是 AR 的截断异构体，其中一部分缺乏配体结合域，在没有循环雄激素的情况下仍然保持持续激活，从而促进癌细胞增殖。因此，AR-Vs 不仅被认为有助于对抗雄激素治疗的耐药性，而且有助于接受联合治疗的患者对放射治疗的耐药性，通过促进 DNA 修复。AR-Vs，如 AR-V7，与患者的不良临床结局相关；然而，迄今为止，试图特异性抑制或预防 AR-Vs 的形成的尝试都没有成功。因此，迫切需要新的治疗策略来解决 AR-Vs 的致癌作用，这可能导致致命形式的前列腺癌。通过调节剪接体来破坏选择性剪接是一种潜在的治疗途径；然而，我们对剪接体的生物学及其对前列腺癌的贡献的理解仍然不完整，这反映在缺乏针对剪接体的治疗剂上。在这篇综述中，作者概述了目前对剪接体在前列腺癌进展中的作用的理解，并探讨了操纵选择性剪接以改善患者治疗的治疗效用。
