Cellular plasticity and the neuroendocrine phenotype in prostate cancer

Abstract

The success of next-generation androgen receptor (AR) pathway inhibitors, such as abiraterone acetate and enzalutamide, in treating prostate cancer has been hampered by the emergence of drug resistance. This acquired drug resistance is driven, in part, by the ability of prostate cancer cells to change their phenotype to adopt AR-independent pathways for growth and survival. Around one-quarter of resistant prostate tumours comprise cells that have undergone cellular reprogramming to become AR-independent and to acquire a continuum of neuroendocrine characteristics. These highly aggressive and lethal tumours, termed neuroendocrine prostate cancer (NEPC), exhibit reactivation of developmental programmes that are associated with epithelial-mesenchymal plasticity and acquisition of stem-like cell properties. In the past few years, our understanding of the link between lineage plasticity and an emergent NEPC phenotype has considerably increased. This new knowledge can contribute to novel therapeutic modalities that are likely to improve the treatment and clinical management of aggressive prostate cancer.

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

“…These cancers almost universally have loss-of-function alterations in RB1 and TP53 and often include amplifications in the MYC family of genes and altered expression of epigenetic regulators (Beltran et al, 2011; Beltran et al, 2016; George et al, 2015; Poirier et al,2015). Further, conversion to a neuroendocrine phenotype has emerged as a mechanism of treatment resistance in prostate and lung cancers (Davies et al, 2018; Oser et al, 2015). Transcriptional profiling of primary human prostate epithelial populations revealed that advanced prostate cancer subtypes vary in their enrichment of a prostate basal stem cell signature with small cell neuroendocrine prostate cancer (SCNPC) being the most stem-like.…”

EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

“…NEPCs are instead characterized by immunoreactivity to clinical neuroendocrine (NE) markers such as chromogranin A, synaptophysin, CD56, and neuron-specific enolase (NSE), although these are not specific. At the molecular level, these tumors are often characterized by RB1 and PTEN losses and TP53 mutations or deficiencies, which have been associated in preclinical studies with androgen independence [8, 12, 13], as well as increased expression/activity of aurora kinase A and N-Myc [6, 14, 15]. Therefore, while most castration-resistant adenocarcinomas (adeno-CRPCs) remain dependent on AR signaling [16], clinical and preclinical data support the androgen-independence of NEPCs [4, 5].…”

The heat shock protein 70 inhibitor VER155008 suppresses the expression of HSP27, HOP and HSP90β and the androgen receptor, induces apoptosis, and attenuates prostate cancer cell growth

“…4 As resistance also occurs frequently applying these drugs, it remains necessary to develop novel therapeutic options. 4 As resistance also occurs frequently applying these drugs, it remains necessary to develop novel therapeutic options.…”

“…Thereby, the key risk factors for PCa occurrence and progression include genetic factors, increasing age and nutrition. 3 Further targeting of the androgen receptor (AR) axis using novel therapeutics like abiraterone acetate and enzalutamide enhances survival for a limited time but also leads to resistance 4 emerging from the development of new substances. 2 However, ADT resistance occurs in a large number of patients within 2 to 3 years, is known as incurable metastatic castration-resistant PCa (mCRPC), and is associated with a poor prognosis.…”