1. Nat. Rev. Urol. doi:10.1038/nrurol.2018.22
Figure 1 Emerging resistance mechanisms to next-generation androgen receptor pathway inhibitors
Figure 1 | Emerging resistance mechanisms to next-generation androgen receptor pathway inhibitors. a | Increasing disease burden following primary prostate cancer therapy (for example, radical prostatectomy and/or radiotherapy) is indicated by rising PSA levels and/or radiographical progression and is treated with hormonal therapy. When hormonal therapy fails, the resulting castration-resistant prostate cancer (CRPC) is treated with next-generation androgen receptor (AR) pathway inhibitors (ARPIs; abiraterone acetate or enzalutamide). However, after an initial decrease in PSA levels, resistance mechanisms rapidly lead to disease recurrence and ultimately death. The majority of patients relapse owing to the reactivation of AR signalling and the presence of AR-driven adenocarcinomas, accompanied by rising PSA levels. A subset of patients manifest with AR-indifferent disease (dotted line), which is characterized by low PSA levels and can exhibit a phenotype of neuroendocrine differentiation — that is, a type of lineage plasticity. The clinical features and proposed molecular drivers of each resistance mechanism are shown. Note that these resistance mechanisms are not mutually exclusive, and some degree of overlap occurs among these mechanisms in both model systems and patient tumours. b | The reactivation of AR signalling is the predominant mechanism of resistance of prostate cancer to hormonal therapy. However, the clinical introduction of next-generation ARPIs (abiraterone and enzalutamide) has fuelled the occurrence of aggressive, heterogeneous, and adaptive clones of cancer cells. Clinical observations suggest that these adaptive clones can decrease their dependence on AR signalling and, instead, rely on AR-indifferent compensatory mechanisms, such as glucocorticoid receptor bypass and lineage plasticity, for growth and survival. The proportion of AR-active and AR-indifferent prostate cancers has changed considerably since the clinical introduction of next-generation ARPIs in 2012 (Refs 24,202). NEPC, neuroendocrine prostate cancer.
Davies, A. H. et al. (2018) Cellular plasticity and the neuroendocrine phenotype in prostate cancer
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