Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors

Abstract

Purpose: The androgen receptor axis inhibitors (ARPI) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown Experimental Design: In a prospective trial MATCH-R (NCT02517892), 59 mCRPC patients underwent whole exome sequencing (WES) and/or RNA-sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 mCRPC patients underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher's exact tests. Results: WES analysis indicated that no single-gene genomic alterations was strongly associated with primary resistance. RNA-seq analysis showed that AR gene alterations and expression levels were similar between responders and non-responders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. Conclusions:Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs’ resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation

Identification of Molecular Markers Associated with Prostate Cancer Subtypes: An Integrative Bioinformatics Approach

“…The percentage of genes participating directly or indirectly in the AR activity increased from 47% for those shared between MP1 and MP2 (7 over 15 genes) to 78% (7 over 9 genes) for genes common to PCa-and CRPCgene lists. These results confirmed the essential role of AR in regulating PCa cells growth and proliferation during the early stages of the oncogenesis, as well as in the resistance acquisition [3,74]. It has been reported that the anti-androgen therapy pressure exerted on the intrinsic cellular heterogeneity of PCa tissues led to the selection of tumour cells showing AR gene alterations or epigenetic perturbation of its regulated pathways [8,11].…”

“…The significant efforts made to study the molecular mechanisms involved in PCa progression identified molecular alterations potentially relevant for improving the clinical management of patients [73,74]. Over the past decade, the use of new drugs inhibiting the AR axis improved the treatment of mPCa and some forms of CPRC, but these chemicals have led to increased CRPC with neuroendocrine features that are still incurable [3,51].…”

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis

“…[5][6][7][8] About 80% of the time, castration resistance is dependent upon reacquired androgen receptor signaling. 9,10 Several resistance mechanisms exist, including AR amplification and mutation, expression of constitutively active AR splice variants such as AR-V7, GR-mediated bypass, and increased endogenous autocrine or paracrine-mediated androgen availability. [11][12][13][14][15][16][17][18] In addition, lineage plasticity relieves a requirement for AR signaling, and is associated with loss of AR expression, rendering tumor cells unresponsive to androgen blockade, resulting in the development of neuroendocrine prostate cancer (NEPC), and double-negative prostate cancer.…”