Hsp90 Inhibition Overcomes Hormone Resistance in Some Aggressive Prostate Cancers
The second-generation heat shock protein 90 (hsp90) inhibitor onalespib may be beneficial for men with prostate cancer that no longer responds to androgen deprivation therapy, according to preclinical research conducted in cells and mice.1
When prostate cancer becomes resistant to androgen-deprivation therapy, it may be due to alternative splicing of the androgen receptor. Specifically, the androgen receptor variant 7 (AR-V7), the most common androgen receptor variant, may be involved.
"We call hsp90 inhibitors network drugs because they tackle several of the signals that are hijacked in cancer all at once, across a network rather than just a single signalling pathway. These drugs can hit cancer harder than those targeting only one protein, and look promising for preventing or overcoming drug resistance,” said Professor Paul Workman, chief executive of The Institute of Cancer Research, in London, United Kingdom.
"Our study has found that hsp90 inhibition can specifically stop resistance to hormone treatments in prostate cancer through a completely new mechanism of action involving the processing of messenger RNA.
"It's an exciting discovery which adds a string to the bow of these cancer drugs, and means they could work against prostate cancers that have otherwise stopped responding to treatment."
The study findings suggest that hsp90 inhibitors could be effective in prostate cancers that have become resistant to treatment and started to metastasize. Using prostate cancer cell lines injected into mice, the researchers found that hsp90 inhibitors have the ability to overcome the malfunctions in the androgen receptor that often occur in hormone-resistant prostate cancer. Furthermore, inhibiting hsp90 blocked the production of abnormal forms of the androgen receptor, which can be an effective treatment in itself.
The study's new insights on hsp90 in drug-resistant prostate cancers open up potential new routes to cancer treatment based on blocking this or related proteins.
The study was mainly funded by the Wellcome Trust, a London-based biomedical research charity.
Hsp90 inhibitors are already in clinical trials for several types of cancer. This study suggests that they may benefit men with prostate cancer who currently have few treatment options.
1. Ferraldeschi R, Welti J, Powers MV, et al. Second-generation HSP90 inhibitor onalespib blocks mRNA splicing of androgen receptor variant 7 in prostate cancer cells [published online ahead of print May 1, 2016]. Cancer Res. doi:10.1158/0008-5472.CAN-15-2186.