Moffitt researchers contribute to discovery of mechanism leading to drug resistance in prostate cancer

TAMP, FL. — Prostate cancer is the most common cancer in men in the United States. Many patients can live long lives thanks to early detection and treatment with androgen deprivation therapy. 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 uncover a mechanism by which prostate cancer cells become resistant through molecular modification of the androgen receptor protein and identify a potential treatment 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 lower 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 significantly improves survival, but almost always leads to recurrent disease called castration-resistant prostate cancer. Scientists have discovered that resistance is primarily due to the reactivation of androgen receptor signaling through various mechanisms, and they have developed new drugs, such as enzalutamide and abiraterone, to overcome this resistance. Unfortunately, patients eventually develop resistance to these drugs in a relatively short period of time. Several resistance mechanisms to these newer generation drugs have been identified, but these changes are not present in all patients, suggesting additional resistance mechanisms exist.

Moffitt’s research team, in collaboration with scientists from 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 lab experiments focusing on the molecular modifications of the androgen receptor and its interactions 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 a chemical acetyl group is added. This alteration occurs at a site of the androgen receptor that allows it to become active even in the presence of enzalutamide. These combined events result in a positive feedback loop in which the androgen receptor further increases the level of itself and the ACK1 protein.

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

“These combined observations suggest the importance of these androgen receptor modification events and protein interactions for the development of castration-resistant prostate cancer,” said Nicholas LawrencePh.D., study co-author and senior member of the Department of Drug Discovery

“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 advanced to clinical trials, these data could open up a new therapeutic modality for relapsed castration-resistant prostate cancer patients, a currently unmet need,” added Harshani Lawrence, Ph.D., study co-author and scientific director of Chemical Biology

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

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

About Moffitt Cancer Center
Moffitt is committed to one life-saving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 52 National Cancer Institute Designated Comprehensive Cancer Centers, an award that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest award. With more than 7,500 team members, Moffitt has an economic impact of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.organd follow the momentum facebookTwitterInstagram and YouTube

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