Discussion
Patients with CRPC usually have a poor prognosis, and several drugs have been demonstrated to prolong overall survival, including enzalutamide and abiraterone. However, CRPC patients will eventually become resistant to enzalutamide treatment via AR-dependent or AR-independent mechanisms (Buttigliero, Tucci et al., 2015). In this review, emerging resistance mechanisms based on previous studies were elaborated, including AR signalling pathways, GR-related pathways, WNT, and metabolic mechanisms. Notably, the roles of microRNAs and gene polymorphisms in Enz resistance were emphasized. Some corresponding therapeutic measures were also introduced to provide references for the selection of therapeutic regimens.
The emergence of new technologies, such as high-throughput next-generation sequencing and liquid biopsies, will facilitate the discovery of more drug resistance genes and determine enzalutamide-resistant mechanisms more quickly (Xu, Chen et al., 2019). In addition, the establishment of CRPC patient-derived xenografts (PDXs) from patients resistant to conventional ADT, second-generation AR inhibitors, and chemotherapy are beneficial for finding more effective and specific therapeutic regimens. Notably, all these models, including an AR-null tumour with NE features, were sensitive to dual inhibition of ribosome production and function (Lawrence, Obinata et al., 2018). Notably, prostate cancer is a heterogeneous disease in which different levels of AR expression influence the sensitivity of cells to enzalutamide. Xenograft models indicated that low/no expression AR−/lo CRPC cells were resistant to enzalutamide, while AR-expressing (AR+) CRPC cells were Enz sensitive. Patients with CRPC had both AR+/hi and AR−/lo PCa cells, which should be considered during Enz-resistant treatment (Li, Deng et al., 2018). Given the failure to direct AR-targeted therapies, selective targeted poly(ADP-ribose) polymerase-2 can provide an alternative therapeutic strategy for AR inhibition by disrupting FOXA1 binding rather than directly targeting AR(Gui, Gui et al., 2019).
In conclusion, these emerging mechanisms offer diverse angles for approaching Enz resistance and provide multiple therapeutic regimens for resistant CRPC treatments. Notably, tumour heterogeneity ,individual gene polymorphisms, and the participation of the formation of distinct drug resistance characteristics should be further explored in future studies. Additionally, combination therapies may become potent strategies for Enz-resistant CRPC treatment.