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Androgen receptor mutations that convey resistance to second-generation anti-androgen receptor compounds

Studies in cell culture and in patient samples identified drug resistance mutations that could help guide prostate cancer treatment. In cells, chronic exposure to the anti-androgen receptor compounds Xtandi enzalutamide or ARN-509 resulted in the acquisition of the F876L androgen receptor mutation. In cells with the F976L mutation, the drugs acted as agonists, whereas in wild-type cells the drugs acted as antagonists and inhibited cell proliferation. In circulating tumor DNA obtained from patients' plasma, the mutation was identified after treatment with ARN-509. Next steps include determining the frequency of the mutation in patients receiving second-generation anti-androgen receptor compounds.
Xtandi enzalutamide is marketed by Astellas Pharma Inc. and Medivation Inc. for castration-resistant prostate cancer. ARN-509 from Aragon Pharmaceuticals Inc. is in Phase II testing.

SciBX 6(29); doi:10.1038/scibx.2013.776
Published online Aug. 1, 2013

Patent application filed; licensing status undisclosed

Joseph, J.D. et al. Cancer Discov.; published online June 18, 2013;
doi:10.1158/2159-8290.CD-13-0226
Contact: James D. Joseph, Aragon Pharmaceuticals Inc., San Diego, Calif.
e-mail:
jjoseph@aragonpharm.com