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

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

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.