Editors' ChoiceCancer

A New Achilles Heel for Prostate Cancer

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Science Translational Medicine  18 Sep 2013:
Vol. 5, Issue 203, pp. 203ec155
DOI: 10.1126/scitranslmed.3007556

The growth of prostate cancer is driven by androgen receptor (AR) signaling, which is activated by androgens such as dihydrotestosterone (DHT). This dependence has served as the basis for a number of recent U.S. Food and Drug Administration–approved drugs targeting AR signaling for prostate cancer treatment. Unfortunately, resistance to these therapies inevitably occurs, and patients progress to castration-resistant prostate cancer (CRPC) after prolonged therapy with AR antagonists. A more thorough understanding of the molecular mechanisms underlying treatment resistance could provide the foundation for the development of novel classes of targeted drugs for the treatment of CRPC.

With this in mind, Chang and colleagues were able to demonstrate in a subset of CRPC that a gain-of-function mutation in 3β hydroxysteroid dehydrogenase type 1 (3βHSD1) results in a degradation-resistant version of this enzyme, causing an increase in DHT production and AR activation. Through a series of elegant biochemical, cell-based, and mouse studies, as well as analysis of human CRPC patient samples, Chang and colleagues demonstrated the relevance of this 3βHSD1 mutation to disease progression. They characterized the biochemical, molecular, and biological effects of the mutation on 3βHSD1 expression and function, DHT production, and ligand-dependent AR signaling in culture and in vivo.

The demonstration that a gain-of-function mutation in a metabolic enzyme can drive cancer resistance to targeted molecular therapies, in contrast to the canonical activating mutations in kinases, represents an important paradigm change. Furthermore, this study provides the molecular and biological framework for the development of novel therapeutic strategies for CRPC by targeting a mutant enzyme driving this disease.

K.-H. Chang et al., A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013). [Abstract]

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