Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance

Abstract

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50’s utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance.TP53gene alterations were more common in nonresponders, although this did not reach statistical significance (P= 0.055).ARgene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets—including those linked to low AR transcriptional activity and a stemness program—were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

Loss and revival of androgen receptor signaling in advanced prostate cancer

“…As mentioned above, the different subtypes are not always clearly separated from each other and likely also not stable over time [ 40 ]. Because of this, it has been assumed that they rather represent different stages of a continuous path toward de-differentiation featuring acquisition of stem cell features, AR-loss and -independence at its very end [ 40 , 42 , 43 ]. Thus, the current review focuses on the more general molecular mechanisms involved in the path to AR-negative disease.…”

Single-cell ATAC and RNA sequencing reveal pre-existing and persistent subpopulations of cells associated with relapse of prostate cancer

“…We then hypothesized that we could systematically use gene signatures as a proxy for the presence of PC cells with different transcriptional features in clinical settings. We first interrogated clinical data of CRPC patients treated with ENZ reported in Alumkal et al (Alumkal et al, 2020) . The patients aggregated into two clusters based on our complete signature set ( Figure S5C ), but patients in neither cluster had significantly shorter progression-free survival (PFS; p > 0.05, log-rank test).…”

“…The most frequently characterized mechanisms of PC or CRPC resistance to ARSIs, ADT, or both, revolve around re-establishing AR signaling e.g. via overexpression of AR or AR mutations (Abida et al, 2019; Alumkal et al, 2020; Devlies et al, 2020; He et al, 2018). Additionally, forms of resistance that are indifferent to AR (Handle et al, 2019), more dependent on FGF signaling (Bluemn et al, 2017) or that are AR negative with NEPC-like features (Beltran et al, 2014) are being identified.…”

Dynamics of Cellular Plasticity in Prostate Cancer Progression

“…For example, genetically engineered mouse (GEM) model with inactivation of Pten and Tp53 failed to show any response to abiraterone, and exhibited accelerated progression to treatment-induced neuroendocrine differentiation (Zou et al, 2017 ). A recent single-arm enzalutamide clinical trial revealed that non-responders to enzalutamide treatment exhibits a basal lineage, such as reduced AR transcriptional activity and a neurogenic/stemness program, while a luminal lineage program was activated in responders (Alumkal et al, 2020 ), indicating that there is need to explore the specific factors that regulate de novo enzalutamide resistance.…”

“…These acquired molecular attributes enable the tumor cells to elude the constraints of normal growth, thereby assisting them to thrive and sustain, escape therapeutic pressure and immune surveillance (Zou et al, 2017 ; Vitkin et al, 2019 ; Yuan et al, 2019 ). Likewise, in PCa, cellular plasticity aids the tumor cells to develop resistance against the targeted therapies in several different ways, for instance, by undergoing phenotypic conversions, cellular reprogramming and transition from one cell lineage to another (Beltran and Demichelis, 2015 ; Zou et al, 2017 ; Alumkal et al, 2020 ).…”