The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen-AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide.
Details
Title
Overcoming mutation-based resistance to antiandrogens with rational drug design
Author
Balbas, Minna D. : Memorial Sloan-Kettering Cancer Center Evans, Michael J. : Memorial Sloan-Kettering Cancer Center Hosfield, David J. : University of Chicago Wongvipat, John : Memorial Sloan-Kettering Cancer Center Arora, Vivek K. : Memorial Sloan-Kettering Cancer Center Watson, Philip A. : Memorial Sloan-Kettering Cancer Center Chen, Yu : Memorial Sloan-Kettering Cancer Center Greene, Geoffrey L. : University of Chicago Shen, Yang : Toyota Technological Institute at Chicago Sawyers, Charles L. : Memorial Sloan-Kettering Cancer Center
Funding Information
National Cancer Institute, CA155169 National Institutes of Health, R25-CA096945 National Cancer Institute, CA089489 Virginia and D. K. Ludwig Fund Geoffrey Beene Cancer Research Center MSKCC Experimental Therapeutics Center MSKCC Imaging and Radiation Sciences Bridge Program Toyota Technological Institute at Chicago Howard Hughes Medical Institute Congressionally Directed Medical Research Programs, Physician Research Training Award, PC102106
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