Identification of AR-variant nuclear import pathways in prostate cancer and elucidation of the molecular mechanisms underlying clinical taxane resistance

项目总结/摘要 雄激素受体（AR）信号转导无疑是关键，不仅对乳腺癌敏感，而且对晚期乳腺癌的发生， 去势抵抗性前列腺癌（CRPC）。因此，AR抑制剂如阿比特龙和恩杂鲁胺， 下一代雄激素剥夺疗法（ADT）已经显示出它们在转移性 去势抵抗性PCa（mCRPC）治疗，然而，大多数患者进展是由于 耐药性的发展。雄激素受体变异体已经成为 对这些药物的抵抗力。发现缺乏配体结合结构域的ARv 7和Arv 567剪接变体是 在细胞核中具有组成性活性，因此尽管有AR抑制剂，也能恢复AR功能。目前尚无有效 对于晚期前列腺癌存在治疗方法 化疗我们对肿瘤生物学的更好理解以及我们对 微管靶向药物确实有助于为癌症治疗的新时代铺平道路。我们 已经报道了微管和动力蛋白马达蛋白是AR运输系统所必需的， 核转位和活性，紫杉烷类抑制微管抑制剂下游的AR信号传导。在 此外，我们发现AR铰链区介导与微管的结合存在于ARv 567中， 从ARv 7开始。因此，ARv 7不与微管结合，也不影响其核定位 紫杉烷治疗。这些数据表明，ARv 7赋予对ADT治疗和紫杉烷类药物的抗性， mCRPC的重要治疗方式。迄今为止，临床ARv 7的分子基础赋予了 对治疗的抵抗性很难阐明。因此，研究雄激素受体的作用机制， 迫切需要剪接变体ARv 7核转位和活性，以帮助鉴定新的 mCRPC中对新型雄激素剥夺和紫杉烷类治疗耐药的生物标志物。一个成功 该提案的完成可能会在肿瘤生物学领域产生重要的积极影响， 靶向PCa的药物的治疗应用。

PROJECT SUMMARY/ABSTRACT Androgen receptor (AR) signaling is inarguably pivotal to not only hormone-sensitive but also advanced castration-resistant prostate cancer (CRPC). Therefore, AR inhibitors such as abiraterone and enzalutamide, the next generation of androgen deprivation therapy (ADT) have shown their effectiveness in metastatic castration-resistant PCa (mCRPC) treatment, however, the majority of patients progress due to the development of drug resistance. Androgen receptors variants has emerged as one of the mechanisms of resistance to these drugs. ARv7 and Arv567 splice variants that found lacking the ligand –binding domain are constitutively active in the nucleus and thus restore AR function despite AR inhibitors. Currently no effective treatments exist for advanced prostate cancer and the only available treatment options is taxanes chemotherapy. Our improved understanding of tumor biology and our continued appreciation for what the microtubule targeting agents can do have helped pave the way for a new era in the treatment of cancer. We have reported that microtubules and the dynein motor protein is required as transportation system for AR for its nuclear translocation and activity and that taxanes inhibit AR signaling downstream of microtubule inhibitors. In addition, we identified that the AR hinge region mediates binding to microtubules is present in ARv567 but missing from ARv7. Therefore, the ARv7 does not bind to microtubules nor its nuclear localization is affected by taxane treatment. These data suggest that ARv7 confers resistance to ADT therapy and taxanes, the most important therapeutic modalities in mCRPC. To date, the molecular underpinnings of clinical ARv7 confer resistance to therapy are poorly elucidated. Therefore, investigations on mechanisms of androgen receptor splice variants ARv7 nuclear translocation and activity are urgently needed, in order to help identify novel biomarker of resistance to novel androgen deprivation and taxanes therapies in mCRPC. A successful completion of this proposal may result in an important positive impact in the field of tumor biology and therapeutic applications of drugs that target PCa.