Evolution of the prostate cancer genome towards resistance

Abstract

The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metastasis spreading and high mortality, a state referred to as castration resistant prostate cancer (CRPC). The technological advances in next generation sequencing have enabled the deep genomic and epigenomic characterization of both the hormone naïve and CRPC states, leading to the definition of molecular subclasses of prostate cancer that could inform the clinicians on therapeutic strategies. These studies also shed light on the mechanisms driving resistance to therapy. CRPCs adapt to androgen receptor (AR) signaling impairment-which follows first-line therapies as androgen deprivation or AR targeting-by restoring the nuclear receptor signaling by means of multiple mechanisms. Alternatively, tumor cells might become resistant to targeted therapies by exploiting lineage plasticity and activating alternative pathways. This review will discuss the main mechanisms leading to the emergence of resistance to therapy in prostate cancer patients in the context of genomic and molecular features of CRPC and on their causal role in the development of resistance.

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

“…[56]. NCOR1 and NCOR2 are transcriptional corepressors that negatively regulate androgen receptor (AR) signalling and androgen-induced cell proliferation [57][58][59]; losses in these genes increase with disease progression and are associated with anti-androgen and ADT resistance [60,61]. TP53 loss may also predict inferior responses to novel androgen signalling inhibitors (ASIs), such as enzalutamide and abiraterone, in CRPC [62].…”

Endocrine Disruptors and Prostate Cancer

“…AR deregulation plays a central role in the onset and progression of PCa to an advanced metastatic disease [7,8]. The mechanism for abnormal AR activation includes somatic AR missense mutation that have been found most frequently first in the LBD and after in the NTD sequence [46,47].…”

“…Commonly, the diagnosis of PCa is made based on elevated plasmatic blood levels of PSA (>4 ng/mL). The androgenic hormones regulate normal prostate gland growth and function by interacting with the androgen receptor (AR), whose gene expression in PCa appears to be deregulated; this plays a central role in development and metastatic progression [7,8]. PCa is considered an androgen-dependent cancer [9,10], its growth requires androgens, such as testosterone (T) or the more potent dihydrotestosterone (DHT), and it was noted that androgen deprivation therapy (ADT) led to prostate tumor regression in up to 80% of cases [11].…”