Adaptive auto‐regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer

Abstract

Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in > 25 fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts; however, when supraphysiologic androgen is acutely replaced. Cell synchronization/anti-androgen response document this is due to AR binding to replication complexes (RC) at origin of replication sites in early G1 associated with licensing/restricting DNA for single round of duplication during S-phase. When CRPC cells are acutely exposed to supraphysiologic androgen, adaptively increased nuclear AR is over-stabilizes preventing sufficient degradation in mitosis inhibiting DNA re-licensing and thus death in the subsequent cell cycle. These mechanistic results and the fact that AR/RC binding occurs in metastatic CRPCs directly from patients provides a paradigm shifting rationale for bipolar androgen therapy (BAT) in patient progressing on chronic androgen ablation. BAT involves giving sequential cycles alternating between periods of acute supraphysiologic androgen followed by acute ablation to take advantage of vulnerability produced by adaptive auto-regulation and binding of AR to RC in CRPC cells. BAT therapy is effective in xenografts and based upon positive results has entered clinical testing.

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

“…The findings might help explain why a new paradigm for treating patients with PCa, referred to as bipolar ADT (67), in which patients undergoing chemotherapy cycle through ADT followed by a supraphysiological dose of androgen, proved more beneficial than ADT alone. Because the function of AR in DNA replication is to help repair double-strand breaks, it has been argued that binding of testosterone to AR under supraphysiological conditions could prevent its normal function of repairing double-strand breaks, which, in turn, can lead to cell cycle failure and programmed cell death (43,68), as seen in patients who responded to bipolar ADT. However, it has also been reported by others (69) that supraphysiological levels of androgens can induce cell cycle arrest and up-regulate markers of cellular senescence in human PCa cells.…”

Treatment strategies for DNA repair-deficient prostate cancer

“…In the setting of castrationresistance, prostate cancer cells significantly elevate levels of AR expression as an adaptive mechanism, in order to continue to express the androgen-regulated genes needed for growth [48]. In the setting of amplified AR levels, flooding the cell with supraphysiological levels of testosterone can paradoxically result in cell-cycle arrest and double-strand DNA breaks [49]. In vivo models have shown that tumors can regress with the administration of high-dose testosterone therapy, but eventually tumors re-adapt to the high testosterone environment over time [50].…”

Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor–Positive Breast Cancer Models with a Distinct Mechanism of Action

“…Gao and colleagues (41) described the role of AR as a tumor suppressor in castration-resistant prostate cancer (CRPC) cells by inhibiting DNA replication-related genes via the recruitment of hypophosphorylated Rb. In addition, the clinical and preclinical efficacy seen with high-dose androgen therapy in CRPC was also attributed to androgen-induced stabilization of AR, which prevents the relicensing of DNA for replication and subsequent cell-cycle progression (58,59). In the current study, the AR-mediated suppression of ESR1 and its downstream pathway, along with the suppression of DNA replication-and cell cycle-related genes seen with RAD140 treatment suggest a distinct mechanism of action of this SARM in AR/ER þ breast cancer cells.…”