Study Reveals Mechanism Behind Drug Resistance in Prostate Cancer

Understanding the Role of the Androgen Receptor

A recent study has investigated how the amplification of the androgen receptor in prostate cancers contributes to drug resistance, pinpointing a crucial protein within this biological pathway. The prostate, an essential gland in the male reproductive system, secretes fluids that constitute semen. Its normal development relies on androgens, hormones that bind to androgen receptors on prostate cells. However, these hormones also play a significant role in promoting the growth of prostate cancers.

Targeted Therapies and Drug Resistance

To combat advanced prostate cancer, scientists have developed targeted therapies that inhibit the binding of androgens to their receptors. Despite their effectiveness, these therapies can lead to drug resistance, resulting in castration-resistant prostate cancer. This form of cancer often overcomes anti-androgen medications by amplifying the androgen receptor gene, allowing cancer cells to respond to androgens again. As drug resistance becomes increasingly common, understanding its mechanisms is essential for developing effective strategies against it.

Research Findings on Anti-Androgen Resistance

A team from the United States conducted research to uncover the biological mechanisms underlying anti-androgen resistance in prostate cancers, with their findings published in eLife. The researchers began by examining prostate cancer cells exhibiting similar expressions of the androgen receptor. Initial experiments revealed that despite comparable receptor expression levels, there was a significant variance in the transcriptional output of the androgen receptor gene. In a mouse model, cells with high androgen receptor gene output formed tumors that demonstrated significantly greater resistance to anti-androgen drugs compared to those with lower output.

Role of GREB1 in Drug Resistance

Utilizing advanced screening techniques, the researchers identified that cells with elevated androgen receptor output exhibited upregulation of the GREB1 gene. Further experiments established GREB1’s critical role, showing that this protein enhances androgen receptor activity and promotes resistance to anti-androgen drugs. Reducing GREB1 expression in cells with high androgen receptor output resulted in increased sensitivity to androgen receptor-targeting medications.

Implications of the Study

This study concluded that GREB1 is integral to the mechanism by which prostate cancer cells amplify the androgen receptor gene, leading to drug resistance. The upregulation of GREB1 increases the transcriptional output of the androgen receptor, ultimately contributing to heightened resistance against anti-androgen therapies. This discovery provides valuable insights into the biology regulating androgen receptor expression and highlights GREB1 as a potential therapeutic target. Future development of GREB1-targeting drugs may enhance the efficacy of anti-androgen receptor-targeted treatments for prostate cancer.

Written by Branson Chen, MSc

Reference: Lee E, Wongvipat J, Choi D, Wang P, Lee YS, Zheng D, Watson PA, Gopalan A, Sawyers CL. GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance. eLife. 2019 Jan 15;8:e41913.