Prostate cancer is the most common cancer among men in the United States. Many patients can live long lives through early detection and treatment with androgen deprivation therapy. However, despite the benefits of this therapy, almost all patients develop drug resistance and disease recurrence over time.
In a new paper published in the journal Science Translational Medicine, Moffitt Cancer Center researchers uncover the mechanism by which prostate cancer cells become resistant through molecular modification of the androgen receptor protein and identify a potential treatment approach that can overcome this resistance.
Androgen deprivation therapy has been the primary treatment for prostate cancer 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 methods that target androgen receptor signals.
Androgen deprivation significantly improves survival, but almost always leads to recurrence of a disease called castration-resistant prostate cancer. Scientists have found that resistance is mainly due to reactivation of androgen receptor signaling through various mechanisms, and have developed new drugs such as enzalutamide and abiraterone to overcome this resistance.
Unfortunately, patients also end up developing resistance to these drugs in a relatively short period of time. Several mechanisms of resistance to these new generation drugs have been identified, but these modifications are not present in all patients, suggesting the existence of additional resistance mechanisms.
Moffitt’s research team, in collaboration with scientists at Washington University in St. Louis, wanted to identify alternative mechanisms of resistance to enzalutamide and abiraterone in prostate cancer patients. They conducted a series of laboratory experiments focused on molecular modifications of the androgen receptor and its interaction with other proteins and DNA.
They found that the androgen receptor is chemically modified in two different places. First, a phosphate group is added to the androgen receptor protein by a protein called ACK1. This chemical modification allows for a second modification in which an acetyl chemical group is added. This modification occurs at the site of the androgen receptor that allows it to become active even in the presence of enzalutamide. As a result of these combined actions, a positive feedback loop occurs, during which the androgen receptor further increases the level of itself, as well as the ACK1 protein.
The researchers confirmed the importance of these molecular changes in mice. They demonstrated that treatment of enzalutamide/abiraterone-resistant prostate tumors in mice with Moffitt’s ACK1 inhibitor called (R)-9b, which targets ACK1, suppresses tumor growth and reduces expression of ACK1, the androgen receptor, and other key androgen receptor-regulated genes. .
Importantly, the researchers also showed that ACK1 and modified androgen receptor expression levels were higher in tissue samples from prostate cancer patients than in normal prostate tissues, and their expression increased over the course of cancer progression.
“These collaborative observations demonstrate the importance of these androgen receptor modification events and protein interactions in the development of castration-resistant prostate cancer,” said Nicholas Lawrence, Ph.D., co-author of the study and senior fellow in drug discovery.