Abstract
Duplication of an AR enhancer occurs in most patients with CRPC and promotes disease progression.
Major finding: Duplication of an AR enhancer occurs in most patients with CRPC and promotes disease progression.
Concept: AR enhancer gain promotes CRPC cell survival and desensitizes cells to hormone deprivation therapy.
Impact: AR duplication may represent a mechanism by which androgen inhibitor resistance can develop.
Androgen receptor signaling underlies prostate tumorigenesis, and in advanced castration-resistant prostate cancer (CRPC) increased AR activity (often via AR amplification) can promote resistance to androgen deprivation. Two related studies identified an AR enhancer that is gained in advanced prostate cancer to drive CRPC. Takeda and colleagues identified an amplicon approximately 650 kb centromeric to the AR gene that was commonly amplified in CRPC tumors, but not localized tumors. Chromosome conformation capture revealed that this putative enhancer region interacted with the AR promoter. This AR enhancer was enriched for H3K27 acetylation in CRPC tumors. The enhancer was required for CRPC cell survival, and AR enhancer knock-in was sufficient to confer castration resistance in androgen-sensitive cells. Viswanathan and colleagues identified the same duplicated AR enhancer through linked-read whole-genome sequencing in 23 metastatic CRPC (mCRPC) samples and analysis of cell-free DNA from 86 patients with mCRPC. AR enhancer gain was detected in all 12 post-progression biopsy samples, suggesting that it may be a common cause of androgen inhibitor resistance, and AR enhancer amplification could also be observed in cell-free DNA. Further, the AR enhancer duplication was associated with structural variations that inactivated the tumor suppressor CDK12. Other structural variations were also observed that resulted in inactivation of tumor suppressors including PTEN. Gains in the AR enhancer or gene promoter upregulated AR to drive AR signaling and CRPC. Taken together, these studies identify an AR enhancer that can be amplified to promote castration resistance and disease progression in patients with prostate cancer.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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