Editors' ChoiceCancer

The ARt of inhibiting AR

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Science Translational Medicine  25 Sep 2019:
Vol. 11, Issue 511, eaaz3707
DOI: 10.1126/scitranslmed.aaz3707


Blocking MED1 phosphorylation is an alternative strategy to inhibit androgen receptor (AR), the main driver of prostate cancer.

Androgen hormones drive prostate cancer progression by activating the androgen receptor (AR). The hormone/AR complex travels to the nucleus, where it binds specific sites in the DNA to control vital cellular processes. Given their tumor-promoting role, reducing androgen concentrations or blocking AR signaling are the main approaches to treat prostate cancer. In most cases, androgen deprivation strategies provoke tumor regression, yet resistance eventually develops, and disease relapses as castration-resistant prostate cancer (CRPC). In many cases of CRPC, androgen-AR signaling persists despite treatment. In a recent publication, Rasool et al. reported that inhibition of cyclin-dependent kinase 7 (CDK7) and its substrate, mediator of RNA polymerase II transcription subunit 1 (MED1), is an alternative strategy to block persistence of AR signaling in prostate cancer.

MED1 is a key transcriptional coactivator for AR; however, the exact mechanisms by which AR interacts with MED1 have remained unclear. Rasool et al. used a technique called chromatin immunoprecipitation with high-throughput sequencing, which identifies DNA binding sites for proteins of interest, to show that MED1 physically engages AR to specific sites of the DNA called super-enhancers. The authors then used a series of molecular techniques to show that AR transcriptional activity requires MED1 phosphorylation. Because AR signaling persists in CRPC, the research team questioned whether phosphorylated MED1 (p-MED1) is a hallmark of resistance and progression. They determined that chronic exposure of prostate cancer cells to the AR antagonist enzalutamide causes p-MED1 to accumulate. Additionally, the nuclear phosphorylated form of MED1 was highly abundant in samples isolated from patients with aggressive disease.

By treating cells with a series of kinase inhibitors and performing gene ablation experiments, the authors figured out that CDK7-mediated MED1 phosphorylation is indispensable for AR transcriptional activity. An in vitro cytotoxicity assay and testing in tumor models showed that THZ1, an inhibitor for CDK7, may be a potential therapy for prostate cancer addicted to AR signaling.

Persistent activation of the AR is a major driver of therapeutic resistance in prostate cancer. Identifying molecular adaptations that elicit higher transcriptional activity of AR is of high clinical relevance to reduce disease burden. The finding that the CDK7/p-MED axis enhances AR transcriptional activity may be particularly important for cancers with constitutively active AR and /or amplified AR, which are clinically challenging.

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