Scientists design an ACK1 inhibitor that suppresses prostate cancer growth


In a paper published in Cancer Cell, researchers at Moffitt Cancer Center reports a new epigenetic mechanism that contributes to castration-resistant prostate cancer, a finding that further extends our knowledge of this deadly disease.

Castration-resistant prostate cancer is when the cancer has spread beyond the prostate and is no longer responding to standard treatment. Most prostate cancer-related deaths are a result of castration-resistant prostate cancer. The growth of prostate cancer is often driven by androgens, a group of hormones that primarily control the development and maintenance of male characteristics. An important therapeutic strategy is inhibiting androgen activity either by surgically removing the testicles or by using medicines that block androgens. This strategy is often effective in the early stage of treatment. However, the disease can progress to metastatic castration-resistant prostate cancer within a few years. What drives this progression remains largely unknown, and this hinders the development of novel therapies.

The aim of the new study is to better understand the mechanism of metastatic castration-resistant prostate cancer. Dr. Nupam Mahajan, a researcher at Moffitt Cancer Center who led the study, and colleagues conducted a series of experiments in vitro and in vivo. They found that a tyrosine kinase called ACK1 (or TNK2) is able to induce phosphorylation of histones -- proteins that package DNA into nucleosomes. This phosphorylation affects the region of the androgen receptor gene, resulting in increased levels and activity of the androgen receptor. The androgen receptor is known to play a critical role in the progression of prostate cancer to metastatic castration-resistant prostate cancer. Taken together, the results demonstrate that ACK1 contributes to prostate cancer progression by inducing phosphorylation, which is a well-studied epigenetic modification. With this knowledge, the researchers hypothesized that targeting ACK1 may help combat metastatic castration-resistant prostate cancer.

Next, the researchers designed an ACK1 inhibitor, (R)-9bMS. The results confirmed that (R)-9bMS could suppress prostate cancer growth, even when the cancer was resistant to the anti-androgen medicine enzalutamide. (R)-9bMS inhibited phosphorylation of the androgen receptor gene, therefore reducing its levels and activity.

Most patients with castration-resistant prostate cancer do not respond to enzalutamide, according to study first author Dr. Kiran Mahajan. ACK1 inhibitor represents a new potential treatment for these patients.
 
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