Consecutive molecular changes in the androgen receptor may contribute to drug resistance, which can be blocked by an ACK1 inhibitor

Prostate cancer is the most common cancer in men in the United States. Many patients can live a long time due to early detection and androgen deprivation treatment. However, despite the benefits of this therapy, almost all patients will eventually develop drug resistance and recurrent disease. In a new article published in Science Translational MedicineMoffitt Cancer Center researchers reveal a mechanism by which prostate cancer cells become resistant through molecular modification of the androgen receptor protein and identify a potential therapeutic approach that could overcome this resistance.

Androgen deprivation therapy has been the mainstay of prostate cancer treatment for decades. The goal of this therapy is to reduce the levels of hormones called androgens that stimulate the growth of prostate cancer cells through surgical or medical approaches that target androgen receptor signaling. Androgen deprivation therapy dramatically improves survival, but almost always leads to a recurring disease called castration-resistant prostate cancer. Scientists have found that resistance is mainly due to reactivation of androgen receptor signaling through different mechanisms, and they have developed new drugs, such as enzalutamide and abiraterone, to overcome this resistance. Unfortunately, patients also eventually develop resistance to these drugs in a relatively short period of time. Several mechanisms of resistance to these next-generation drugs have been identified, but these changes are not present in all patients, suggesting the existence of additional resistance mechanisms.

The Moffitt research team, in collaboration with scientists from Washington University in St. Louis, wanted to identify alternative mechanisms of resistance to enzalutamide and abiraterone in patients with prostate cancer. prostate. They performed a series of laboratory experiments focusing on the molecular changes of the androgen receptor and its interactions with other proteins and DNA. They found that the androgen receptor chemically changes at two distinct sites. First, a phosphate group is added to the androgen receptor protein by a protein called ACK1. This chemical modification allows a second modification during which an acetyl chemical group is added. This modification occurs on a localization of the androgen receptor which allows it to become active, even in the presence of enzalutamide. These events combined result in a positive feedback loop in which the androgen receptor further increases its levels, as well as those of the ACK1 protein.

The researchers confirmed the importance of these molecular changes in the mouse experiments. They demonstrated that treating enzalutamide/abiraterone-resistant prostate tumors in mice with an ACK1 inhibitor designed by Moffitt called (R)-9b that targets ACK1 suppressed tumor growth and reduced expression levels of ACK1, androgen receptor, and additional key genes regulated by the androgen receptor. Importantly, the researchers also showed that the expression level of ACK1 and the altered androgen receptor was higher in tissue samples from patients with prostate cancer than in normal prostate tissue, and their expression increased throughout cancer progression.

“These observations combined suggest the importance of these androgen receptor altering events and protein interactions for the development of castration-resistant prostate cancer,” said Nicholas Lawrence, Ph.D., co-author of the study and a senior member of the drug discovery department.

“The identification of an ACK1 kinase inhibitor that has the ability to thwart both the modifications and the fact that an ACK1 inhibitor has not yet reached clinical trials, these data could open a new therapeutic modality for patients with recurrent castration-resistant prostate cancer, a currently unmet need,” added Harshani Lawrence, Ph.D., study co-author and Chief Scientific Officer of Chemical Biology.

Drs. Nicholas and Harshani Lawrence, both medicinal chemists, are the inventors of (R)-9b.

This study was supported by grants received from the National Institutes of Health (R01CA208258, R01CA227025, R50CA211447), the Prostate Cancer Foundation (17CHAL06), and the Department of Defense (W81XWH-15-1-0059).

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