TY - JOUR
T1 - Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer
AU - Boudadi, Karim
AU - Antonarakis, Emmanuel S.
N1 - Funding Information:
fUNdiNg: ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973. The authors confirm that the funders had no influence over the study design, content of the article, or selection of this journal.
Publisher Copyright:
© 2016, © 2016 SAGE Publications.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone.
AB - Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone.
KW - abiraterone
KW - castration-resistant prostate cancer
KW - enzalutamide
KW - novel androgen-directed therapy
KW - resistance
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U2 - 10.4137/CMO.Ss34534
DO - 10.4137/CMO.Ss34534
M3 - Review article
AN - SCOPUS:85029791821
SN - 1179-5549
VL - 10s1
SP - 1
EP - 9
JO - Clinical Medicine Insights: Oncology
JF - Clinical Medicine Insights: Oncology
ER -