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.