Androgen Receptor Burden and Poor Response to Abiraterone or Enzalutamide in TP53 Wild-Type Metastatic Castration-Resistant Prostate Cancer

Abstract

Androgen receptor (AR) molecular perturbations in liquid biopsy specimens (circulating tumor cells [CTCs] and circulating tumor DNA [ctDNA]) from patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with poorer outcomes on the AR signaling inhibitors (ARSis) abiraterone or enzalutamide, with contradictory claims regarding the clinical use of AR splice variant 7 (AR-V7) or AR amplification status. [1][2][3][4] By using comprehensive liquid biopsy AR profiling, 5 we previously demonstrated how AR perturbations lost prognostic value when correcting for tumor burden estimates and clinical variables. 6 Consistent with others' findings, 4 we observed that AR-driven biomarkers were outperformed by TP53 alterations, noting that 71.3% and 97.9% of patients carried relevant AR-driven biomarkers at baseline and progression, respectively. 6 We therefore speculate that long-term chemical castration, alongside the cancer treatment trajectory, will eventually lead to perturbed AR biomarker output in all patients. In this scenario, multiple biomarker assessments of AR are necessary to identify ARSi-sensitive patients.

Genomic Profiling in ctDNA Revealing Complicated Resistance Mechanism of Olaparib and Abiraterone as Salvage Therapy in Prostate Cancer: A Case Report

“…Disease progression was mainly due to a secondary AR-V7 overexpression as well as the epithelial-mesenchymal transition of prostate cells as in parallel with reported investigations [17]. In addition, androgen receptor ampli cation or gain of function mutations of AR, as observed in ctDNA of this patient, would also continuously activate downstream AR signaling pathway overcoming extrinsic androgen inhibition [18,19].…”

Novel PGK1 determines SKP2-dependent AR stability and reprograms granular cell glucose metabolism facilitating ovulation dysfunction

“…Ubiquitination generally promotes protein degradation and represents a classical, regulated PTM, with a critical role in both physiological and pathological processes, such as reproduction, growth and development, signal transduction, and tumourigenesis [47] , [48] , [49] , [50] . AR is a nuclear receptor family member with a high-affinity site for chromatin that regulates transcriptional activity, and the ubiquitination ligase system plays a key role in mediating AR activation/reactivation [51] , [52] , [53] . The E3 ligase SKP2 not only plays a vital role in protein degradation via the proteasome but also contributes to cell cycle regulation [54] , [55] , [56] .…”

Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer

“…3.7. The RRM2 signature may predict enzalutamide resistance in prostate cancer circulating tumor cells Circulating tumor cells (CTCs) detach from the primary or secondary tumor sites and invade the bloodstream, and they have been reported to be useful prognostic biomarkers to aid prostate cancer diagnosis, treatment decision making, and patient follow-up (Chung et al, 2019;De Laere et al, 2019;Nimir et al, 2019). The prognostic value of CTCs collected by the epithelial marker-dependent method CellSearch has been established in the context of metastatic PC (Hegemann et al, 2016).…”