A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer

Abstract

The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again. Importantly, AR mutations are more frequently detected in this type of cancer. By analyzing tumor biopsy mRNA from CRPC patients who had developed resistance to CYP17 inhibitor treatment, we have identified a novel nonsense mutation (Q784*) at the ligand binding domain (LBD) of AR, which produces a C-terminal truncated AR protein that lacks intact LBD. This AR-Q784* mutant is transcriptionally inactive, but it is constitutively expressed in the nucleus and can bind to DNA in the absence of androgen. Significantly, our results show that AR-Q784* can heterodimerize with, and enhance the transcriptional activity of, full-length AR. Moreover, expressing AR-Q784* in an AR positive PCa cell line enhances the chromatin binding of endogenous AR and the recruitment of p300 coactivator under the low androgen condition, leading to increased cell growth. This activity of AR-Q784* mimics the function of some AR splice variants, indicating that CYP17 inhibitor treatment in CRPC may select for LBD-truncated forms of AR to restore AR signaling.

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…AR is a nuclear receptor transcription factor with the three-dimensional crystal structure containing the ligand-binding domain (LBD) and DNA binding domain (DBD). It is essential to aggressiveness and progression of PCa [ 101 ]. Androgens activate AR signaling by binding to AR to drive the growth as well as metastasis and simultaneously suppress apoptosis of PCa cells [ 102 – 104 ].…”

Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges

“…Han et al [ 53 ] identified the novel AR mutant Q874 in biopsy tissues from patients who had acquired resistance to a CYP17 inhibitor. The mutant protein has no transcriptional activity by itself, similar to other AR splice variants, but forms a heterodimer with the full-length AR to enhance its transcriptional activity.…”

Bedeutung der Androgenrezeptor-Spleißvariante AR-V7 für Prognose und Therapie des fortgeschrittenen Prostatakarzinoms

“…Natürlich vorkommende AR-Mutationen, welche mit dem Verlust der LBD einhergehen, wie die Nonsense-Mutation AR-Q640X bzw. AR-Q784*, sind allerdings im klinischen Alltag extrem selten und können nicht für die hohe Rate von CRPC verantwortlich gemacht werden [16,17]. Eine der wichtigsten Entdeckungen der letzten Jahre ist die Fähigkeit von PCa-Zellen, durch alternatives Spleißen der AR-Vorläufer-messenger RNA (mRNA) neben dem normalen AR auch noch vermehrt AR-Spleißvarianten (AR-V) zu generieren, welche keine funktionelle LBD mehr exprimieren [5 -7] ( ▶ Abb.…”