# Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer

## TL;DR

This study identifies Plexin D1 as a new target in neuroendocrine prostate cancer, which could help treat treatment-resistant cases.

## Contribution

The novel contribution is identifying PLXND1 as a key player in neural lineage plasticity and a potential therapeutic target in NEPC.

## Key findings

- PLXND1 is highly expressed in NEPC and correlates with neuroendocrine markers.
- PLXND1 inhibition suppresses NEPC cell proliferation and tumor growth.
- HSP70 regulates PLXND1 stability, and its inhibition reduces NEPC growth.

## Abstract

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 is highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression is associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibit neural lineage pathways, suppressing NEPC cell proliferation, PDX tumor organoid viability, and xenograft tumor growth. Mechanistically, the chaperone protein HSP70 regulates PLXND1 protein stability through degradation, and inhibition of HSP70 decreases PLXND1 expression and NEPC organoid growth. In summary, our findings suggest that PLXND1 could be a new therapeutic target and molecular indicator for NEPC.