Molecular Mechanisms of Enzalutamide Resistance in Prostate Cancer

Abstract

Compensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in prostate cancer. After hydroxyflutamide and bicalutamide were used in therapy of prostate cancer over many years, novel anti-androgen enzalutamide showed improved clinical activity. However, enzalutamide resistance develops over a certain time period, and molecular mechanisms responsible for this process are heterogeneous. As with other anti-androgens, these mechanisms include alterations of AR but also may be associated with overexpression of oncogenes which should be targeted by novel therapies. Androgen receptor splice variants have been frequently described in patients who developed enzalutamide resistance. Mutant AR F876L has been detected in patients who are resistant to enzalutamide. Glucocorticoid receptor overexpression has been observed in patient tissues and in pre-clinical models of enzalutamide resistance. There is a heterogeneous picture of enzalutamide resistance in prostate cancer and, therefore, the development of appropriate post-enzalutamide treatment remains a challenge.