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Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in Castration-Resistant Prostate Cancer

ABSTRACT: Illumina gene array analyses of prostate cancer cell lines that had acquired resistance to Enzalutamide (MDV3100). mRNA analyses of four cell lines (CWR-R1, LAPC-4, LNCaP, and VCAP) cells that were either untreated, treated for 48hrs with Enz (short-term), or continuously grown in Enzalutamide for >6 months.

ORGANISM(S): Homo sapiens

SUBMITTER: Donald J Vander Griend Donald Vander Griend Steven Kregel

PROVIDER: E-GEOD-78201 | ArrayExpress | 2016-02-24

SECONDARY ACCESSION(S): GSE78201PRJNA312915

REPOSITORIES: GEO, ArrayExpress

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Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

Project description: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. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment

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Expression data from LNCaP cells treated with DHT and enzalutamide

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2013-04-01 | E-GEOD-44905 | ArrayExpress

Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in Castration-Resistant Prostate Cancer

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Comparison of poly(A) and capture RNA-seq: controlled degradation in vitro

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Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)

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2015-04-09 | E-GEOD-64143 | ArrayExpress

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