Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

Abstract

Prostate cancer (PCa) has become the most common form of cancer in men in the developed world, and it ranks second in cancer-related deaths. Men that succumb to PCa have a disease that is resistant to hormonal therapies that suppress androgen receptor (AR) signaling, which plays a central role in tumor development and progression. Although AR continues to be a clinically relevant therapeutic target in PCa, selection pressures imposed by androgendeprivation therapies promote the emergence of heterogeneous cell populations within tumors that dictate the severity of disease. This cellular plasticity, which is induced by androgen deprivation, is the focus of this review. More specifically, we address the emergence of cancer stem-like cells, epithelial-mesenchymal or myeloid plasticity, and neuroendocrine transdifferentiation as well as evidence that demonstrates how each is regulated by the AR. Importantly, because all of these cell phenotypes are associated with aggressive PCa, we examine novel therapeutic approaches for targeting therapy-induced cellular plasticity as a way of preventing PCa progression.

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer

“…For example, multiple studies have shown that AR inhibition through ADT can promote EMT. Conversely, aberrant AR signaling has been indicated in driving EMT in CRPC (reviewed in [48]). Similarly to these studies that highlight the cell-context-dependent regulation of EMT by AR, a previous study reported that Snail overexpression induced neuroendocrine prostate cancer (NEPC) differentiation in prostate cancer cells [49].…”

Clinical and molecular features of treatment‐related neuroendocrine prostate cancer

“…Clinically, it overlaps with “anaplastic prostate carcinoma” or “AVPC,” which are characterized by extensive visceral metastases, short response duration to ADT, sensitivity to platinum‐containing chemotherapy and poor prognosis . t‐NEPC develops as a consequence of lineage plasticity, a phenomenon in which tumor cells acquire phenotypic characteristics of a cell lineage whose survival is no longer regulated by a certain drug target . The incidence of t‐NEPC has been rising rapidly as a result of the increasing use of potent AR pathway inhibitors, and it is now imperative to study the molecular characteristic of this aggressive subtype and identify specific molecular targets.…”

“…13,14 t-NEPC develops as a consequence of lineage plasticity, a phenomenon in which tumor cells acquire phenotypic characteristics of a cell lineage whose survival is no longer regulated by a certain drug target. 15 The incidence of t-NEPC has been rising rapidly as a result of the increasing use of potent AR pathway inhibitors, and it is now imperative to study the molecular characteristic of this aggressive subtype and identify specific molecular targets. Recent integrative genomic analysis and novel in vivo models of t-NEPC have identified several key molecular features of NEPC.…”

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

“…Due to the maintenance of AR activity, survival benefits are achieved by re-targeting AR signaling with next-generation AR-directed therapeutics, though responses are generally measured in months rather than years(10,11). While resistance is again often accompanied by persistent AR activity, prolonged and effective AR suppression can induce epithelial-to-mesenchymal-transition (EMT) (12–14), acquisition of stem-like cell characteristics(13,15–17), and trans-differentiation into an AR-null neuroendocrine phenotype. There are also significant complications and quality of life issues that arise with long-term ADT(18,19).…”