Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer

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Significance

Men with aggressive prostate cancer that has stopped responding to conventional treatment could potentially benefit from a new class of cancer drug designed to overcome drug resistance, a new study by Ferraldeschi et al published in Cancer Research suggests. Researchers led by The Institute of Cancer Research in the UK found that Onalespib, a Hsp90 inhibitors, specifically target and inactivate a mechanism commonly used by prostate cancer cells to evade the effects of standard treatment.

The findings provide vital information about the role of Hsp90 in drug-resistant prostate cancers, and open up potential new routes to cancer treatment based on blocking this or related proteins. The research team found that Hsp90 inhibitors countered the effect of malfunctions in the androgen receptor, which often occur in prostate cancer cell resistance to hormone treatments. The authors suggests that Hsp90 inhibitors [potential ‘resistance-busting’ drugs] could be effective in prostate cancers that have become resistant to treatment and started metastasized.

Researchers investigated the effect of onalespib (as a Hsp90 inhibitor) on human cancer cells expressing androgen receptor variant, AR-V7. Results showed Hsp90 inhibition reduced production of AR-V7 by changing the way that messenger RNA molecules carrying the code for AR-V7 are processed. Hsp90 inhibition also reduced the levels of the normal androgen receptor, and other important prostate cancer molecules called AKT and GR. Indeed second-generation HSP90 inhibitor onalespib altered the splicing of at least 557 genes in prostate cancer cells, including AR

Hsp90 inhibition can specifically stop resistance to hormone treatments in prostate cancer, through a new mechanism of action involving the processing of messenger RNA. Hsp90 inhibitors are already in clinical trials for several types of cancer, and this research highlight the potential benefit men with prostate cancer who have otherwise run out of treatment options.”

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REFERENCE

Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells. Ferraldeschi R, Welti J, Powers MV, Yuan W, Smyth T, Seed G, Riisnaes R, Hedayat S, Wang H, Crespo M, Nava Rodrigues D, Figueiredo I, Miranda S, Carreira S, Lyons JF, Sharp S, Plymate SR, Attard G, Wallis N, Workman P, de Bono JS. Cancer Res. 2016 ;76(9):2731-42.

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Figure Credit: (Prof. Johann de Bono, Institute of Cancer Research-UK)

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