Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer

Abstract

Castration resistant prostate cancer (CRPC) continues to be androgen receptor (AR) driven. Inhibition of AR signaling in CRPC could be advanced using state-of-the-art biophysical and biochemical techniques. Structural characterization of AR and its complexes by cryo-electron microscopy would advance the development of N-terminal domain (NTD) and ligand-binding domain (LBD) antagonists. The structural basis of AR function is unlikely to be determined by any single structure due to the intrinsic disorder of its NTD, which not only interacts with coregulators but likely accounts for the constitutive activity of AR-splice variants (SV), which lack the LBD and emerge in CRPC. Using different AR constructs lacking the LBD, their effects on protein folding, DNA binding, and transcriptional activity could reveal how interdomain coupling explains the activity of AR-SVs. The AR also interacts with coregulators that promote chromatin looping. Elucidating the mechanisms involved can identify vulnerabilities to treat CRPC, which do not involve targeting the AR. Phosphorylation of the AR coactivator MED-1 by CDK7 is one mechanism that can be blocked by the use of CDK7 inhibitors. CRPC gains resistance to AR signaling inhibitors (ARSI). Drug resistance may involve AR-SVs, but their role requires their reliable quantification by SILAC–mass spectrometry during disease progression. ARSI drug resistance also occurs by intratumoral androgen biosynthesis catalyzed by AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase), which is unique in that its acts as a coactivator of AR. Novel bifunctional inhibitors that competitively inhibit AKR1C3 and block its coactivator function could be developed using reverse-micelle NMR and fragment-based drug discovery.

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

“…A variety of mechanisms have been identified that contribute to resistance to novel AR signaling inhibitors, including: AR gain of function point mutations, constitutively active AR transcript variants, AR gene amplification, and most recently, amplifications of an enhancer upstream of the AR gene that regulates AR mRNA expression (2,(11)(12)(13)(14). Furthermore, posttranslational modifications of the AR or changes in AR coactivators also contribute to persistent AR function (15).…”

AKR1B1 and AKR1B10 as Prognostic Biomarkers of Endometrioid Endometrial Carcinomas

“…NRF2 binds to and up-regulates the expression of the antioxidant response elements of these genes. This is supported by studies showing that NRF2 inducers elevate AKR1B1 and AKR1B10 expression and that NRF2 signaling is activated by chemicals that produce reactive oxygen species [ 46 , 47 , 48 ].…”

AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer

“…Oxidative stress is recognized by nuclear erythroid 2-related factor 2 (NRF2), which binds to the antioxidant response elements of numerous antioxidant/detoxifying genes, including the AKR genes AKR1B1 and AKR1B10, thus upregulating their expression. Studies that support this explanation showed that NRF2 inducers increase AKR1B1 and AKR1B10 expression and that NRF2 signaling is activated by chemicals that produce reactive oxygen species [60][61][62]. The exact mechanism by which an increased AKR1B1 expression is associated with a better survival of patients with HGSC is currently unknown and requires further studies.…”