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Emerging mechanisms of enzalutamide resistance in prostate cancer

Abstract

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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Figure 1: Therapy-induced mechanisms of resistance in metastatic prostate cancer.
Figure 2: Structure and functions of the AR, AR variants and the glucocorticoid receptor.

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Acknowledgements

F.C. and S.J. hold grants from Fonds Wetenschappelijk Onderzoek-Vlaanderen (G.0684.12N and G.0830.13N), the Belgian federal government (National Cancer Plan KPC_29_023) and a Concerted Research Action of the KU Leuven (GOA/15/017).

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F.C., C.H., S.P. and T.V.d.B. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission. L.S., H.V.P. and S.J. contributed to review and/or editing of the manuscript before submission.

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Correspondence to Frank Claessens.

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The authors declare no competing financial interests.

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Claessens, F., Helsen, C., Prekovic, S. et al. Emerging mechanisms of enzalutamide resistance in prostate cancer. Nat Rev Urol 11, 712–716 (2014). https://doi.org/10.1038/nrurol.2014.243

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