How does prostate cancer acquire drug resistance?

Cancer
prostate cancer

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A recent study explored how amplification of the androgen receptor in prostate cancers leads to drug resistance and identified an important protein in this biological pathway.

The prostate is a gland of the male reproductive system that plays a role in secreting fluids which make up semen. Normal development of the prostate relies on a hormone called androgen, which binds to androgen receptors on prostate cells. But androgen is also known to be involved in driving the growth of prostate cancers. Scientists have developed targeted therapies against androgen receptor, which are drugs that block the binding of androgen to the receptor as a way to effectively treat advanced prostate cancer.

Targeted therapies can cause drug resistance

These targeted therapies can cause drug resistance, however, leading to castration-resistance prostate cancer. This type of prostate cancer mostly overcomes these anti-androgen drugs by amplifying the androgen receptor gene so that the cancer cells are once again able to respond to androgen. With drug resistance becoming more prevalent, scientists need to gain a better understanding of it to develop strategies to address the problem. A group from the United States investigated the biological mechanisms behind anti-androgen resistance in prostate cancers and published their findings in eLife.

The authors of this study first examined prostate cancer cells that have a similar expression of the androgen receptor. Their first experiments showed that although expression of the receptor was similar, there was varying transcriptional output (i.e., production of RNA, which is an intermediary for the receptor to be made) of the androgen receptor gene. When comparing cells with high vs low androgen receptor gene output, the high output ones formed tumors that were significantly more resistant to anti-androgen drugs in a mouse model.

Prostate cancer amplifies gene that contributes to drug resistance

Using advanced screening methods, the researchers found that cells with high androgen receptor output had upregulation of the GREB1 gene. Additional experiments confirmed the importance of GREB1 by showing that this protein promotes androgen receptor activity and facilitates anti-androgen drug resistance. When reducing the expression of GREB1 in cells with high androgen receptor output, the cancer cells become more sensitive to an androgen receptor-targeting drug.

This study determined that GREB1 is involved in how prostate cancer cells amplify the androgen receptor gene to develop drug resistance. GREB1 is upregulated in order to increase transcriptional output of the androgen receptor, which ultimately contributes to increased anti-androgen drug resistance. This discovery sheds light on the biology behind the regulation of androgen receptor expression and identifies GREB1 as an important target. This will hopefully lead to the development and use of GREB1-targeting drugs, which may sensitize prostate cancers to anti-androgen receptor-targeted therapy.

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.

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