title: Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer.
abstract: Prostate cancer is a tumor addicted to androgen receptor (AR) signaling, even in its castration resistant state, and recently developed antiandrogen therapies including Abiraterone acetate and enzalutamide effectively target the androgen signaling axis, but there is ultimately recurrence to lethal disease. Development of advanced castration-resistant prostate cancer (CRPC) is a biological consequence of lack of an apoptotic response of prostate tumor cells to androgen ablation. Taxanes represent the major clinically relevant chemotherapy for the treatment of patients with metastatic CRPC; unfortunately, they do not deliver a cure but an extension of overall survival. First-generation taxane chemotherapies, Docetaxel (Taxotere), effectively target the cytoskeleton by stabilizing the interaction of β-tubulin subunits of microtubules preventing depolymerization, inducing G2M arrest and apoptosis. Shifting the current paradigm is a growing evidence to indicate that Docetaxel can effectively target the AR signaling axis by blocking its nuclear translocation and transcriptional activity in androgen-sensitive and castration-resistant prostate cancer cells, implicating a new mechanism of cross-resistance between microtubule-targeting chemotherapy and antiandrogen therapies. More recently, Cabazitaxel has emerged as a second-line taxane chemotherapy capable of conferring additional survival benefit to patients with CRPC previously treated with Docetaxel or in combination with antiandrogens. Similar to Docetaxel, Cabazitaxel induces apoptosis and G2M arrest; in contrast to Docetaxel, it sustains AR nuclear accumulation although it reduces the overall AR levels and FOXO1 expression. Cabazitaxel treatment also leads to downregulation of the microtubule-depolymerizing mitotic kinesins, MCAK, and HSET, preventing their ability to depolymerize microtubules and thus enhancing sensitivity to taxane treatment. The molecular mechanisms underlying taxane resistance involve mutational alterations in the tubulin subunits, microtubule dynamics, phenotyping programming of the epithelial-to-mesenchymal transition landscape, and the status of AR activity. This chapter discusses the mechanisms driving the therapeutic resistance of taxanes and antiandrogen therapies in CRPC, and the role of AR in potential interventions toward overcoming such resistance in patients with advanced metastatic disease.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Martin
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Department of Pathology and Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA. Electronic address: nkypr2@email.uky.edu.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000517:prevention & control; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000726:Androgen Antagonists; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel
keywords: Androgen receptor; Castration-resistant prostate cancer; Chemotherapy; Taxanes