Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

Jun 9, 2016Oncotarget

Cellular androgen levels affect how enzalutamide activates the F877L mutant androgen receptor

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Abstract

Enzalutamide treatment can become ineffective due to a mutation in the androgen receptor known as F877L.

Castration-resistant prostate cancer (CRPC) often progresses despite therapies that target androgen receptor signaling.
The F877L mutation in the androgen receptor can transform enzalutamide from an antagonist to an agonist.
Cellular androgen levels affect the agonistic activity of enzalutamide on the mutant F877L androgen receptor.
The BET bromodomain inhibitor JQ-1 was found to inhibit both androgen and enzalutamide activation of the F877L mutant.
JQ-1 also reduced growth in CRPC tumors expressing the F877L mutation in animal models.

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Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) - the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.

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Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

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