Acetylation and Activation of AR K609 and ACK1 Promote Resistance to Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer
Background: Prostate cancer is the leading cancer diagnosis in men and one of the leading causes of cancer-related death in the United States.1 Castration-resistant prostate cancer (CRPC) is the radiographic progression and/or rising prostate-specific antigen (PSA) following androgen deprivation therapy (ADT).2 CRPC patients exhibit resistance to second-generation androgen receptor antagonists such as enzalutamide.2 Unfortunately, there is currently no curative therapy available for CRPC. While the mechanism of CRPC is not completely understood, recent studies have shown changes in androgen receptor protein (AR) expression are found almost exclusively in CRPC and primarily account for the development of its resistance.1,2,3 These findings suggest potential novel therapeutic targets for CRPC.
Objective(s): To explore how the acetylation and activation of AR K609 and ACK1 promote resistance to androgen receptor antagonists in CRPC.
Search Methods: An online search was conducted using the PubMed database for relevant articles published between 2017 and 2023 using the following keywords: “castration-resistant prostate cancer”, “CRPC treatment”, “androgen receptor antagonist in prostate cancer”, and “CRPC mechanism”.
Results: ACK1 has been shown to promote the growth and survival of cancer cells by activating signaling pathways involved in cell proliferation and survival.2 A unique feedback mechanism where ACK1 mediated phosphorylation results in the acetylation of K609 which then upregulates AR and ACK1 expression in CRPC has been identified.2 Understanding this mechanism and disrupting it could be utilized as a target for potential therapy in the future.2 High ACK1 expression is associated with increased tumor aggressiveness, resistance to AR antagonists, and higher risk of disease progression and mortality.2 A small molecule inhibitor (R)-9b was created in order to suppress AR in CRPC. This (R)-9b has been shown to greatly reduce AR expression and suppress CRPC growth in human prostate organoids and mice.4-7 Although the effectiveness of (R)-9b has been demonstrated in multiple trials, there have been no human trials conducted to date.
Conclusion: In conclusion, studies have demonstrated that higher expression of ACK1 is associated with a worse prognosis for patients with castration-resistant prostate cancer. The unique feedback mechanism between acK609-AR and ACK1, which leads to increased expression of both AR and ACK1, could potentially serve as a target for therapy. Although the ACK1 small molecule inhibitor (R)-9b has shown efficacy in human organoids and mice, further investigation is needed before human trials can be conducted. While the overexpression of ACK1 is linked to CRPC, better understanding of other mechanisms involved in the tumor growth of CRPC could also help with the development of potential therapies.
- Davies A, Conteduca V, Zoubeidi A, Beltran H. Biological Evolution of Castration-resistant Prostate Cancer. Eur Urol Focus. 2019;5(2):147-154. doi:10.1016/j.euf.2019.01.016
- Sawant M, Mahajan K, Renganathan A, et al. Chronologically modified androgen receptor in recurrent castration-resistant prostate cancer and its therapeutic targeting. Sci Transl Med. 2022;14(649):eabg4132. doi:10.1126/scitranslmed.abg4132
- Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. Nat Rev Dis Primers. 2021;7(1):9. Published 2021 Feb 4. doi:10.1038/s41572-020-00243-0
- Ghildiyal R, Sawant M, Renganathan A, et al. Loss of Long Noncoding RNA NXTAR in Prostate Cancer Augments Androgen Receptor Expression and Enzalutamide Resistance. Cancer Res. 2022;82(1):155-168. doi:10.1158/0008-5472.CAN-20-3845
- Nguyen DT, Yang W, Renganathan A, et al. Acetylated HOXB13 Regulated Super Enhancer Genes Define Therapeutic Vulnerabilities of Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022;28(18):4131-4145. doi:10.1158/1078-0432.CCR-21-3603
- Mahajan K, Malla P, Lawrence HR, et al. Cancer Cell. 2017;31(6):790-803.e8. doi:10.1016/j.ccell.2017.05.003
- Sridaran, D., Chouhan, S., Mahajan, K. et al. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nat Commun 13, 6929 (2022). https://doi.org/10.1038/s41467-022-34724-5