Neuroendocrine prostate cancer (NEPC) is a high-risk, lethal subset of disease, that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. However, the clinical features of NEPC are poorly defined. Now, researchers from the Flinders Health and Medical Research Institute in South Australia report they have identified a new mechanism in which prostate cancer cells can “switch” character and become resistant to therapy.

Their findings are published in Cell Reports, in a paper titled, “Post-transcriptional Gene Regulation by MicroRNA194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer.”

Flinders University associate professor Luke Selth, PhD, from the Flinders Health and Medical Research Institute. [The Hospital Research Foundation]
It is well established that some tumors show increased cellular “plasticity” in response to new or stressful conditions, such as cancer therapy, said Luke Selth, PhD, lead researcher and associate professor at the Flinders Health and Medical Research Institute.

“Increased cellular plasticity is increasingly recognized as a key feature by which prostate cancers become resistant to therapy and progress to a lethal stage,” he added.

The findings reveal that a particular molecule, the microRNA “miR-194,” can enhance this plasticity in prostate cancer, leading to the emergence of NEPC.

“Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of NEPC, a phenomenon associated with enhanced cell plasticity,” noted the researchers. “Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity.”

The researchers observed that by targeting miR-194, they were able to hinder the growth of prostate cancer models with neuroendocrine features.

While further study is needed before clinical application, Selth added, it “nevertheless provides us with important new insights into how prostate cancers ‘evolve’ in response to therapy.”

There are currently no effective treatments for NEPC, with estimates up to 15% of men developing this aggressive subtype of prostate cancer after hormonal treatment—a major problem because these men face “very poor outcomes.”

“By revealing another regulator of prostate cancer cell plasticity that can promote evolution of tumors, our study highlights why prostate cancer is so difficult to cure.”

The researchers concluded, “…our study demonstrates that miR-194 can promote adenocarcinoma-NE transdifferentiation and the growth of NEPC by targeting a network of genes that includes the lineage-defining transcription factor FoxA1. These findings deliver
unique molecular insights into lineage plasticity in PCa and provide impetus to investigate the potential of targeting miR-194 as a therapy for NEPC.”