Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

Abstract

Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.

Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes

“…N-Myc is not normally expressed in the lineage of prostate epithelial cells but is overexpressed in a subset of CRPC adenocarcinomas and the majority of NEPC. Especially, a subset of CRPCs that become independent of AR signaling and develop neuroendocrine features through lineage plasticity [ 117 ] are associated with poor prognosis and aggressive disease and are partly driven by aberrantly expressed N-Myc. Berger et al [ 118 ] performed integrative analysis of the transcriptome, cistrome, and interactome of N-Myc in prostate cancer.…”

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance

“…abiraterone or enzalutamide) 28 . There are several proposed mechanisms of resistance that lead to CRPC including alterations in AR which permit activity in low-androgen settings, alterations in pathways downstream of AR, and increased signaling through other signaling pathways allowing for AR independence 29 . Despite some recent progress in developing new treatments for CRPC, average survival at this advanced disease stage is approximately 3 years 30 .…”

A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation

“…Although NEPC can occur de novo , the majority of the NEPC patients arise from castration‐resistant prostate cancer (CRPC) patients treated with hormone therapy, radiotherapy or chemotherapy. Long term treatment results in the trans‐differentiation of adenocarcinoma cells into treatment‐induced NEPC [41,42] . NEPC is characterized by decreased expression of androgen receptor ( AR ) and AR target genes, and increased expression of neuroendocrine markers synaptophysin ( SYP ), chromogranin A ( CHGA ) and neuron‐specific enolase ( ENO2 ) [1,41,43] .…”

“…Long term treatment results in the trans‐differentiation of adenocarcinoma cells into treatment‐induced NEPC [41,42] . NEPC is characterized by decreased expression of androgen receptor ( AR ) and AR target genes, and increased expression of neuroendocrine markers synaptophysin ( SYP ), chromogranin A ( CHGA ) and neuron‐specific enolase ( ENO2 ) [1,41,43] . Neuroendocrine differentiation requires multiple epigenetic regulators, [41–44] including EZH2, [1,45] which cooperates with the oncogenic regulator N‐Myc (MYCN) [43,46] to repress AR target genes during neuroendocrine differentiation (NED) [40,43,47] …”