Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer.
In recent years, in castration resistant prostate cancer (CRPC), several new drugs have been approved that prolong overall survival, including enzalutamide and abiraterone, two new-generation hormonal therapies. Despite the demonstrated benefit of these agents, not all patients with CRPC are responsive to treatment, the gain in median progression-free survival with these therapies compared to standard of care is, rather disappointingly, still less than six months and the appearance of acquired resistance is almost universal. Approximately one third of patients treated with abiraterone and 25% of those treated with enzalutamide show primary resistance to these agents. Even if the mechanisms of resistance to these agents are not fully defined, many hypotheses are emerging, including systemic and intratumoral androgen biosynthesis up-regulation, androgen receptor (AR) gene mutations and amplifications, alteration of pathways involved in cross-talk with AR signaling, glucocorticoid receptor overexpression, neuroendocrine differentiation, immune system deregulation and others. The aim of this paper is to review currently available data about mechanisms of resistance to abiraterone and enzalutamide, and to discuss how these mechanisms could be potentially overcome through novel therapeutic agents.
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy. Electronic address: consuelo.buttigliero@gmail.com.
Consuelo
C
Buttigliero
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Marcello
M
Tucci
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Valentina
V
Bertaglia
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Francesca
F
Vignani
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Paolo
P
Bironzo
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Massimo
M
Di Maio
Department of Oncology, Medical Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Giorgio Vittorio
GV
Scagliotti
D000728:Androgens / Q000378:metabolism*; D000736:Androstenes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005784:Gene Amplification; D006801:Humans; D008297:Male; D009154:Mutation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015854:Up-Regulation
D000728:Androgens; D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone
Abiraterone; Enzalutamide; Mechanisms of resistance; Prostate cancer