Antiandrogen withdrawal in castrate‐refractory prostate cancer

Sartor, A. Oliver; Tangen, Catherine M.; Hussain, Maha; Eisenberger, Mario A.; Parab, Minoti; Fontana, Joseph A.; Chapman, Robert A.; Mills, Glenn; Raghavan, Derek; Crawford, E. David

doi:10.1002/cncr.23473

Cited by 125 publications

(74 citation statements)

References 32 publications

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“…Moreover, the antiandrogen withdrawal syndrome, which is known to occur in patients after cessation of antiandrogens such as hydroxyflutamide, bicalutamide, or nilutamide treatment is known to be partly explained by the occurrence of mutations in the AR that convert the antagonists into agonists (49). Similar mechanisms have been anticipated for enzalutamide.…”

Section: Discussionmentioning

confidence: 85%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

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Section: Discussionmentioning

confidence: 85%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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“…Thereafter, this phenomenon has been widely observed in several kinds of antiandrogens (3,4), and the concept of 'alternative antiandrogen therapy' has been developed based on these findings; that is, it has been shown to be useful to use other antiandrogens for patients whose disease becomes refractory to primary MAB (3,13,14). Although the detailed molecular mechanisms underlying AWS remain largely unknown, some types of mutated AR have been suggested to be involved in AWS (5-9).…”

Section: Discussionmentioning

confidence: 99%

“…Initially, ~90% of patients with advanced prostate cancer favorably respond to MAB therapy; however, androgenindependent (AI) progression ultimately occurs within a few years in the majority of these patients (1,2). During the course of AI progression, a paradoxical phenomenon, 'antiandrogen withdrawal syndrome (AWS)', which is characterized by the improvement of clinical findings associated with prostate cancer following discontinuation of therapeutic antiandrogen, has been shown to occur in 25-50% of patients treated with androgen ablation therapy (3,4).…”

Section: Introductionmentioning

confidence: 99%

The antiandrogen bicalutamide activates the androgen receptor (AR) with a mutation in codon 741 through the mitogen activated protein kinase (MARK) pathway in human prostate cancer PC3 cells

Miyake¹

2010

Oncol Rep

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Abstract. The objective of this study was to assess the effect of antiandrogen on the activation of mutated androgen receptor (AR) and its signaling pathway in prostate cancer. We transfected the AR gene with a point mutation at codon 741 (tryptophan to leucine; W741L) into human androgenindependent prostate cancer PC3 cells lacking the expression of AR, and established PC3 cells overexpressing mutant type AR (PC3/W741L). Changes in the phenotype in these cells were compared to those in PC3 cells transfected with wildtype AR (PC3/Wild) and control vector alone (PC3/Co). There was no significant differences in the growth among PC3/Co, PC3/Wild and PC3/W741L cells. A transactivation assay using these cells showed that bicalutamide activated W741L mutant type AR, but not wild-type AR, while hydroxyflutamide failed to activate either type of ARs. Treatment with specific inhibitors of the MAPK or STST3 pathway (UO126 or AG490, respectively), in contrast to treatment with the Akt pathway inhibitor LY294002, significantly inhibited the dihydrotestosterone-induced activation of both wild-type and mutant ARs; however, activation of W741L mutant AR by bicalutamide was significantly inhibited by treatment with UO126, in contrast to treatment with AG490 or LY294002. Furthermore, treatment of PC3/W741L with bicalutamide, in contrast to treatment with hydroxyflutamide, resulted in significant upregulation of phosphorylated p44/42 MAPK. These findings suggest that the MAPK pathway might be involved in the activation of the AR with a point mutation at codon 741 induced by treatment with the antiandrogen bicalutamide. IntroductionProstate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-specific deaths in men in Western industrialized countries. Despite intensive efforts in the field of prostate cancer research, androgen withdrawal therapy has continued to be the mainstay of treatment for men with advanced prostate cancer since the report by Huggins and Hodges in 1941 (1). In recent years, a novel therapeutic strategy of androgen ablation by combining luteinizing hormone-releasing hormone analog and antiandrogen was introduced as 'maximal androgen blockade (MAB)'. Initially, ~90% of patients with advanced prostate cancer favorably respond to MAB therapy; however, androgenindependent (AI) progression ultimately occurs within a few years in the majority of these patients (1,2). During the course of AI progression, a paradoxical phenomenon, 'antiandrogen withdrawal syndrome (AWS)', which is characterized by the improvement of clinical findings associated with prostate cancer following discontinuation of therapeutic antiandrogen, has been shown to occur in 25-50% of patients treated with androgen ablation therapy (3,4).Several investigators have reported the activation of some types of mutant androgen receptors (ARs) by anti-androgens (5-9). For example, Fenton et al reported that flutamide works as an agonist for T877S and H874Y mutant ARs (6), while Hara et al showed the stimulation of W741...

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“…The AAWS has been more frequently reported in early studies, associated with a longer progression-free survival and greater improvement in quality of life (Dupont et al 1993), probably due to both the different drugs used and the development of more accurate diagnostic techniques. More recent findings suggest that AAWS can be detected in about 20% of patients after cessation of AR blockers, with a median progression-free survival of 3 months (Sartor et al 2008).…”

Section: First-generation Antiandrogens Withdrawal Syndromementioning

confidence: 99%

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Leone

Tucci

Buttigliero

et al. 2018

Endocrine-Related Cancer

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Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castrationresistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on newgeneration hormonal therapies. Several in vitro studies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.

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Antiandrogen withdrawal in castrate‐refractory prostate cancer

Cited by 125 publications

References 32 publications

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

The antiandrogen bicalutamide activates the androgen receptor (AR) with a mutation in codon 741 through the mitogen activated protein kinase (MARK) pathway in human prostate cancer PC3 cells

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

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