Delineating the Role of the Acetyl-CoA Pathway in the Resistance to Anti-Androgen Therapy
Abstract
Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes that are important for fatty acid and cholesterol synthesis, as well as signaling functions through serving as the acetyl group donor for protein acetylation. Acetylation of the androgen receptor (AR) protects the AR protein from proteasomal degradation. Also, chromatin remodeling via histone acetylation facilitates AR signaling activity. Abiraterone and enzalutamide, are the most commonly used drugs in the first-line treatment of metastatic castration-resistant prostate cancer (PC). However, nearly all PC patients ultimately develop resistance to androgen-targeted therapeutics. Despite tremendous efforts in understanding the underlying mechanisms of the resistance, overcoming resistance to therapeutics targeting the AR axis remains an unmet medical need. Our preliminary studies demonstrate, for the first time, that treatment with abiraterone and enzalutamide elevates intracellular levels of acetyl-CoA in PC cells. The addition of exogenous acetyl-CoA, or its precursor acetate, enhances androgen-mediated AR signaling and diminishes the anticancer activity of abiraterone and enzalutamide. We propose to test the novel hypothesis that PC cells upregulate production of acetyl-CoA as an adaptive defense mechanism in response to androgen deprivation. Production of an increased amount of acetyl-CoA ensures efficient acetylation of different components of the AR pathway promoting AR signaling, and thereby contributing to antiandrogen resistance. To test our hypothesis and to address the role of the acetyl-CoA pathway in resistance to therapeutics targeting the AR axis, we propose the following Specific Aims: (1) To delineate the role of the acetyl-CoA pathway in resistance to AR targeting therapeutics; (2) To determine the link between p300/CBP and acetyl-CoA in antiandrogen resistance; and (3) To determine whether expression of acetyl-CoA and proteins regulating acetyl-CoA homeostasis in prostate tumors correlates with clinical response to androgen deprivation therapy. The current application addresses the following FY21 PCRP Overarching Challenge: Define the biology of lethal prostate cancer to reduce death. The projected time to achieve a first patient-related outcome will be within 3 years from the start of the project. By the end of the grant period, we will be able to come out with a panel of novel biomarkers of antiandrogen resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210790
Entities
People
- Vladimir Kolenko
Organizations
- United States Army