In the United States, prostate cancer is the most frequent cancer among males. Because of early discovery and treatment with androgen deprivation therapy, many individuals can live long lives. Despite the benefits of this treatment, almost all patients will develop medication resistance and recurrent disease at some point. Moffitt Cancer Center researchers uncover a process by which prostate cancer cells become resistant through a genetic change of the androgen receptor protein in a new publication published in Science Translational Medicine, as well as a potential therapy option to overcome this resistance.
For decades, androgen deprivation therapy has been the gold standard in the treatment of prostate cancer. Through surgical or medicinal techniques that target androgen receptor signaling, the goal of this therapy is to diminish the quantities of hormones called androgens that encourage prostate cancer cell development. Although androgen restriction therapy improves survival, it almost always leads to castration-resistant prostate cancer, which is a recurring disease. Scientists recognized that resistance is mostly caused by the reactivation of androgen receptor signaling via several methods, and they produced new medications to combat this resistance, such as enzalutamide and abiraterone. Unfortunately, in a relatively short period of time, patients develop resistance to these medications. Several resistance mechanisms to these newer-generation medications have been found, however, not all patients have these alterations, implying that other resistance mechanisms exist.
The Moffitt researchers hoped to find alternate resistance pathways to enzalutamide and abiraterone in prostate cancer patients, so they collaborated with experts from Washington University in St. Louis. They conducted a series of laboratory studies focusing on the androgen receptor’s molecular alterations and interactions with other proteins and DNA. They discovered that the androgen receptor undergoes two chemical modifications. A protein called ACK1 adds a phosphate group to the androgen receptor protein first. This chemical change allows for a second modification, which involves the addition of an acetyl group. This alteration happens at a site on the androgen receptor that allows it to become active even when enzalutamide is present. These actions combine to create a positive feedback loop in which the androgen receptor, as well as the ACK1 protein, increases its own levels.
In animal tests, the researchers validated the importance of these chemical alterations. They found that treating enzalutamide/abiraterone-resistant prostate cancers in mice with (R)-9b, a Moffitt-designed ACK1 inhibitor, slowed tumor growth and reduced expression levels of ACK1, the androgen receptor, and several critical genes regulated by the androgen receptor. Importantly, the researchers discovered that ACK1 and the mutated androgen receptor were expressed at higher levels in prostate cancer tissue samples than in normal prostate tissue and that their expression increased as cancer progressed.
Author: Muhammad Asim