Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit

Abstract

Androgen receptor signaling is critical in the development and progression of prostate cancer, leading to intensive efforts to elucidate all potential points of inflection for therapeutic intervention. These efforts have revealed new mechanisms of resistance and raise the possibility that known mechanisms may become even more relevant in the context of effective androgen receptor suppression. These mechanisms include tumoral appropriation of alternative androgen sources, alterations in androgen receptor expression, androgen receptor mutations, truncated androgen receptor variants, alterations and cross-talk in recruitment of cofactors to androgen receptor binding sites in the genome, and androgen receptor-driven oncogenic gene fusions. New agents such as enzalutamide, EPI-001, androgen receptor-specific peptidomimetics, novel HSP90 inhibitors, and PARP inhibitors, as well as new approaches to cotargeting the androgen receptor pathway, point to the potential for more complete and durable control of androgen receptor-mediated growth.

Figure 1

Figure A - Schematic of the full-length androgen receptor (a) and exon structure of major splice variants (ARV7 (b) and ARV567 (c)). Domains of AR include the amino (N) terminal domain, the DNA binding domain (DBD), the hinge region (HR), and the carboxy (C) terminal ligand-binding domain (LBD). Mutations which occur in specific regions are indicated. Adapted from Green and colleagues (68) with permission from Elsevier. Figure 1B - ADVANCES: Inhibition of AR ligand production: Inhibition of CYP17A by Abiraterone, Orteronel, Galeterone, VT474, or CFG920 suppresses testicular, adrenal and tumoral androgen synthesis. Galeterone can suppress CYP17A, antagonize androgens and reduce AR levels. Abiraterone at high doses can inhibit AR and HSD3B. AR degradation: AR can be destabilized through inhibition of HSP90 binding. AR-cofactor association: Peptidomimetics (e.g. D2) can disrupt AR interaction with cofactors, decreasing AR driven gene transcription. AR antagonism: Enzalutamide and ARN509 block ligand/receptor interactions at the LBD, reduce AR-DNA association and AR nuclear accumulation. EPI-001 blocks AR NTD-coactivator association and nuclear accumulation, and is active against truncated AR variants lacking the C terminal domain (CTD). Adapted from Knudsen K, et al (69)

Figure 1

Figure A - Schematic of the full-length androgen receptor (a) and exon structure of major splice variants (ARV7 (b) and ARV567 (c)). Domains of AR include the amino (N) terminal domain, the DNA binding domain (DBD), the hinge region (HR), and the carboxy (C) terminal ligand-binding domain (LBD). Mutations which occur in specific regions are indicated. Adapted from Green and colleagues (68) with permission from Elsevier. Figure 1B - ADVANCES: Inhibition of AR ligand production: Inhibition of CYP17A by Abiraterone, Orteronel, Galeterone, VT474, or CFG920 suppresses testicular, adrenal and tumoral androgen synthesis. Galeterone can suppress CYP17A, antagonize androgens and reduce AR levels. Abiraterone at high doses can inhibit AR and HSD3B. AR degradation: AR can be destabilized through inhibition of HSP90 binding. AR-cofactor association: Peptidomimetics (e.g. D2) can disrupt AR interaction with cofactors, decreasing AR driven gene transcription. AR antagonism: Enzalutamide and ARN509 block ligand/receptor interactions at the LBD, reduce AR-DNA association and AR nuclear accumulation. EPI-001 blocks AR NTD-coactivator association and nuclear accumulation, and is active against truncated AR variants lacking the C terminal domain (CTD). Adapted from Knudsen K, et al (69)