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Overcoming enzalutamide drug resistance in prostate cancer

Scientists have discovered a molecular pathway that may answer why some prostate cancers can resist an approved cancer drug. The experiments could inform new clinical strategies for patients with castration-resistant prostate cancer.

The study, published in Science Translational Medicine shows that acetylation of the androgen receptor at a specific residue explains why some prostate cancers resist the cancer drug enzalutamide (Xtandi). The authors, based at Washington University in St Louis, also show that a small-molecule compound overcomes resistance and shrinks aggressive prostate tumours in mice.

Therapies that target androgen receptor signalling pathways are the mainstay treatments for patients with early- or later-stage metastatic prostate cancer. Yet patients develop resistance, even to next-generation androgen receptor antagonists such as enzalutamide.

The authors set out to find how enhanced androgen receptor signalling leads to resistance, using cell and mouse models.

Hunting for enzalutamide resistance mechanisms

The authors first used chemical proteomics in castration-resistant prostate (CRPC) cancer cells that were resistant to enzalutamide to uncover molecular mechanisms underlying resistance. The study showed that acetylation at residue K609 of the androgen receptor (acK609-AR), which is in the zinc-finger DNA binding domain, conveyed resistance to enzalutamide. 

Specifically, acK609-AR not only facilitated androgen receptor translocation but also initiated a global transcription program.

Mechanistically, acK609-AR was recruited to enhancer regions of genes encoding the androgen receptor and the ACK1 tyrosine kinase. This process upregulated the transcription of these genes.

Then, the researchers found that ACK1–mediated phosphorylation of residue Y267 of the androgen receptor was necessary for K609-AR acetylation. These modifications kicked off positive feedback loops — both transcriptional and posttranslational — that sustained expression of the androgen receptor and ACK1.

A tumour reducing compound

Next, the authors treated mice with (R)-9b, a small-molecule inhibitor of ACK1. The compound, given by injection or orally, reduced the size of enzalutamide-resistant xenograft tumours. At a molecular level, the compound reduced Y267 phosphorylation and K609 acetylation in the tumours.

Examination of prostate tumour samples from patients showed that the androgen receptor is acetylated in humans, indicating that the pathway is therapeutically relevant. 

Overall, this study uncovers two dependent molecular events — ACK1–mediated phosphorylation of residue Y267 and K609 acetylation of the androgen receptor — that mediate resistance in prostate cancer.

The authors note that “[The] identification of an ACK1 kinase inhibitor that has the ability to thwart both the modifications thus opens a therapeutic modality for patients with recurrent CRPC, a currently unfulfilled need”.

Written by Charlotte Harrison, Science Writer

Image Credit: Canva

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Cancer / drug targets / Prostate Cancer / Resistance