Editors' ChoiceCancer

Prostate cancer loses when androgen receptor can’t stick the landing

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Science Translational Medicine  16 Aug 2017:
Vol. 9, Issue 403, eaao4208
DOI: 10.1126/scitranslmed.aao4208


A small-molecule inhibitor blocks the interaction of the androgen receptor with DNA to target drug-resistant prostate cancer.

The androgen receptor (AR) is the central target in the treatment of advanced prostate cancer (PC). Current therapeutic approaches use inhibitors that block activation of the AR by its ligand and hence prevent AR-driven activation of genes required for PC cell growth. However, resistance develops via numerous mechanisms, including mutations or truncations of the AR that preclude the need for ligand activation. The increased lethality associated with the progression of PC to a drug-resistant state underscores the need to develop new strategies to target the AR. To that end, Dalal et al. explored the utility of a small-molecule inhibitor to prevent the AR from interacting with its final target, DNA.

The authors previously used structure-based virtual screening to identify compounds that could interact with the DNA binding domain (DBD) of the AR. They confirmed that their lead compound, VPC-14449, could prevent full-length AR from transcribing AR-targeted genes and inhibit tumor growth in a mouse model. However, the full utility of VPC-14449 against resistant PC cells was still unknown. Therefore, they tested VPC-14449 on a panel of PC cell lines that had mutations in the cell surface ligand-binding domain (LBD) or expressed AR variants that no longer contained a LBD. In all cell lines tested, VPC-14449 reduced cell growth, demonstrating the utility of this targeting modality against cells that no longer respond to LBD-targeted therapies. The authors also confirmed the ability of VPC-14449 to inhibit an additional panel of clinically relevant mutations in the AR-LBD that are associated with resistance but for which there are currently no available cell lines. They accomplished this by transiently expressing AR with these mutations and testing the transcriptional activity of the mutant AR in the presence of their drug. For every mutant tested, VPC-14449 was inhibitory. Furthermore, the authors tested VPC-14449 in combination with enzalutamide, a drug that targets the AR-LBD and is currently used in the clinic, and demonstrated increased cell killing when the drugs were used in combination.

These studies confirm that alternative AR-targeting approaches are a viable option for drug-resistant PC. The potential synergy seen in the combinatorial studies will be particularly interesting to follow up on because this dual targeting strategy of simultaneously shutting down both ends of the AR signaling cascade could reduce or even eliminate the emergence ability of resistance.

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