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After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.
Financial & competing interests disclosure
This work was supported by grants from NIH T32CA009688 (DC) and T32CA071341 (DD). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
The recent approval of abiraterone (androgen synthesis inhibitor) and enzalutamide (androgen receptor [AR] antagonist), based on randomized clinical trials showing increased survival in pre- and post-chemotherapy metastatic castrate-resistant prostate cancer patients, establishes AR as an important therapeutic target in castrate-resistant prostate cancer.
After initial response, most patients develop progressive disease, with a rising prostate-specific antigen, the AR target gene. In many patients, there may be cross-resistance to abiraterone and enzalutamide. Understanding mechanisms of resistance is necessary for developing better treatments.
Resistance to abiraterone may include reactivation of intratumoral androgen synthesis through increased expression of CYP17 or other enzymes involved in androgen synthesis.
A point mutation F867L in the ligand-binding domain of AR confers resistance to second-generation anti-androgens enzalutamide and ARN-509.
Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone or enzalutamide. Novel agents such as EPI-001 targeting the N-terminal transactivation domain of AR may be effective in inhibiting splice variants.
Glucocorticoid receptor in tumor cells may bypass the need for AR by activating some androgen target genes.
Combination therapy with existing or novel drugs may delay development of resistance.