Table 1.
Summary of mechanisms and approaches of overcoming the enzalutamide resistance in preclinical PCa model.
| Mechanisms of resistance | Targets | Approaches (drugs) | Mechanism of action | Problems and solutions |
|---|---|---|---|---|
| Constitutive AR signaling activation | AR-V | ASC-J9 | Degrades ARs | Unknown other effects |
| BET inhibitors (JQ1, OTX015) | Inhibits expression of ARs | Develop of resistance to BET inhibitor. Combination of BET inhibitor with CDK9 inhibition or/and PARP inhibitor | ||
| AR mutations | AR mutants | ASC-J9 | Degrades ARs | Other effects unknown |
| Transcriptional activities | Darolutamide (ODM-201) | AR antagonist | Unknown | |
| CDK4/6 | CDK4/6 inhibitor (LEE011) | Inhibits AR-induced cell proliferation | Non-specificity (target all proliferative cells) | |
| Bypassing AR signaling | GR | Arylpyrazole compound 15 | GR antagonist | GR signaling is essential for normal functions, and GR antagonists activate AR |
| To increase 11β-HSD2 expression or/and activity | Unknown | Converts cortisol (active form of GR ligands) to cortisone (inactive form of GR ligands) | Unknown | |
| AMFR (A ubiquitin E3-ligase) | Unknown | Degrades 11β-HSD2 | Unknown | |
| Wnt5A | siRNA | Wnt5A knock-down | Unknown | |
| Autophagy | Clomipramine or metformin | Inhibits autophagy | Non-specificity | |
| Intratumoral androgen synthesis | AKR1C3 | Indomethacin | Inhibits conversion of weak androgens to more-active androgens | Validation in human |
| Lineage switching | SOX2 | Unknown | Mediates the lineage plasticity by loss of RB1 and TP53 | Unknown |
| Microenvironmental effects | IL6/JAK/STAT3 | ASC-J9 | Inhibits STAT3 phosphorylation and activation | Other effects unknown |
| IL6 | Inhibits PCa cells with SOCS3 overexpression | Opposite effect in PCa cells without SOCS3 expression | ||
AR, androgen receptor; GR, glucocorticoid receptor; AMFR, autocrine mobility factor receptor; SOCS3, suppressor of cytokine signaling 3; JAK/STAT3, Janus kinase/signal transducer and activator of transcription 3; IL6, interleukin 6; 11β-HSD2, 11β-hydroxysteoid dehydrogenase-2; AKR1C3, aldo-keto reductase family 1 member C3; ASC-J9, 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one; LEE011, a small-molecule inhibitor for CDK4/6; PCa, prostate cancer; CDK, cyclin-dependent kinase.