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Nat Rev Urol. 2014 Dec;11(12):712-6. doi: 10.1038/nrurol.2014.243. Epub 2014 Sep 16.

Emerging mechanisms of enzalutamide resistance in prostate cancer.

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Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, Leuven 3000, Belgium.
Urology, Department of Development and Regeneration, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.


The majority of prostate cancers are hormone-dependent at diagnosis highlighting the central role of androgen signalling in this disease. Surprisingly, most forms of castration-resistant prostate cancer (CRPC) are still dependent on the androgen receptor (AR) for survival. Therefore, the advent of new AR-targeting drugs, such as enzalutamide, is certainly beneficial for the many patients with metastatic CRPC. Indeed, this compound provides a substantial survival benefit-but it is not curative. This Perspectives article describes the different ways through which cancer cells can become resistant to enzalutamide, such as AR truncation and other mutations, as well as by-pass of the AR dependence of prostate cancer cells through expression of the glucocorticoid receptor. The clinical relevance of these mechanisms and emerging questions concerning new therapeutic regimens in the treatment of metastatic CRPC are being discussed.

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