Androgen receptor variation affects prostate cancer progression and drug resistance

Abstract

Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment. We address how these AR splice variants and mutations affect tumor progression and therapeutic resistance and discuss potential novel therapeutic strategies under development. It is hoped that these therapies can be administered with increasing precision as tumor genotyping methods become more sophisticated, thereby lending clinicians a better understanding of the underlying biology of prostate tumors in individual patients.

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

“…3 However, many patients exhibit resistance to androgen deprivation therapy, resulting in mCRPC (metastatic castrate-resistant prostate cancer). 4 The patients with mCRPC have poor survival, suggesting that understanding the mechanism of prostate cancer development and progression is pivotal for discovery of new therapies of prostate cancer.…”

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

“…Flutamide and bicalutamide have been proven to have agonist properties in cells engineered to express higher AR levels (Tran et al 2009). Clones with AR gene amplification are commonly induced in vivo by long-term antiandrogen exposure (McCrea et al 2016).…”

“…Two different phase III trials demonstrated the efficacy of enzalutamide in the treatment of CRCP, both before (Beer et al 2014) and after (Scher et al 2012) docetaxel use. Many different mechanisms have been associated with primary and acquired resistance to enzalutamide (McCrea et al 2016). The development of aberrant truncated AR variants, such as ARV-7 and ARV-567, seems to play a central role in CRCP progression (Buttigliero et al 2015).…”

“…Antonarakis and coworkers reported a significantly lower response rate in patients treated either with enzalutamide or abiraterone who expressed ARV-7 in circulating tumor DNA compared to patients without ARV-7 (0% vs 53%, P = 0.004 for enzalutamide; 0% vs 68%, P = 0.004 for abiraterone) (Antonarakis et al 2014). Furthermore, the activation of alternative growth pathways, independent from AR signaling, along with the cross-talk between AR downstream genes and other steroidal hormone receptors and ligands are probably implicated in disease progression in patients treated with new-generation hormonal therapy (McCrea et al 2016). However, like first-generation NSAA, enzalutamide resistance can also be caused by some point mutations of the full-length AR protein (Liu et al 2017).…”

“…Currently, there is evidence supporting a key role of the AR in all the phases of PCa, and AR and intratumoral steroidogenesis modifications drive the evolution to CRPC. Neoplastic cells acquire the capability to grow in an environment characterized by low androgens levels, because of the upregulation of specific enzymes involved in androgen synthesis, such as CYP17 α-hydroxylase and C17-20-lyase (CYP17), AR gene overexpression and mutations, AR splice variants expression and increased expression of transcriptional coactivators (Buttigliero et al 2015, McCrea et al 2016.…”