Cellular rewiring in lethal prostate cancer: the architect of drug resistance

Abstract

Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K-AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens.

Fig. 1 |. Timeline of treatments for advanced prostate cancer.

Timeline of milestone treatments used for the current management of prostate cancer, in both androgen-responsive and castration-resistant stages. Note how novel therapies include combinatory options such as androgen deprivation therapy (ADT) plus docetaxel (CHAARTED trial, 2015 and STAMPEDE, 2016), ADT plus abiraterone (LATITUDE trial, 2017) or ADT plus enzalutamide (ARCHES trial, 2019). OS, overall survival.

Fig. 2 |. Therapeutic targeting of cell rewiring mechanisms contributing to acquired drug resistance.

Various cellular rewiring pathways contribute to acquired drug resistance; some of these pathways offer potential treatment targets. Key regulatory cascades include the AR, PI3K–AKT, GATA2 and GR pathways. Other pathways that are currently under investigation are mediated by master regulator transcription factors such as SOX2 and ONECUT2. A number of agents (highlighted in red) have been used experimentally to inhibit cellular rewiring mechanisms and have been shown to resensitize drug-resistant cells. AR, androgen receptor; AR-V7, androgen receptor variant 7; BET, bromodomain and extra-terminal domain; BRD4, bromodomain containing protein 4; ECFR, epidermal growth factor receptor; EZH2, enhancer of zeste homologue 2; GATA2, GATA binding protein 2; GR, glucocorticoid receptor; HER2, human epidermal growth factor receptor 2; IGF2, insulin-like growth factor 2; IGFR, insulin-like growth factor receptor; INSR, insulin receptor; LBD, ligand-binding domain; N-T, N-terminal; ONECUT2, one cut homeobox 2; POM121, POM121 transmembrane nucleoporin; RORγ, retinoic acid receptor-related orphan receptor-γ; RTK, receptor tyrosine kinase; SOX2, SRY (sex determining region Y)-box2; SRC1, steroid receptor co-activator 1; SRC2, steroid receptor co-activator 2.

Fig. 3 |. Cellular plasticity and switching phenotypes associated with acquired drug resistance.

A number of distinct phenotypes and molecular pathways are associated with the acquisition of drug resistance. NEPC is characterized by the presence of markers such as chromogranin A and synaptophysin and an AR^low/− status, and is driven by transcription and epigenetic factors such as ONECUT2 and EZH2, among others. CSCs are characterized by a CD44⁺CD133⁺AR^low/−PSA^low/− CK19^low/−HLA^low/− phenotype. EMT is promoted by transcription factors such as SNAIL and SLUG and driven by pathways such as ERG–SRC and PI3K–AKT–mTOR, resulting in a switch in cell expression from E-cadherin to N-cadherin. AR, androgen receptor; CSC, cancer stem cell; EMT, epithelial mesenchymal transition; ERG, ETS transcription factor; EZH2, enhancer of zeste homologue 2; MAPK, mitogen-activated protein kinase; NEPC, neuroendocrine prostate cancer; N-MYC, MYCN proto-oncogene; ONECUT2, one cut homeobox 2; SOX2, SRY (sex determining region Y) box 2; SNAIL, Snail family transcriptional repressor 1; SLUG, Snail family transcription repressor 2; SRC, steroid receptor co-activator; STAT3, signal transducer and activator of transcription 3; TGFβ, transforming growth factor-β.