# Impact of neuroendocrine neoplasm-specific systemic treatments on expression and function of CXCR4 in neuroendocrine tumor cells

## TL;DR

This study investigates how systemic treatments for neuroendocrine tumors affect CXCR4, a protein linked to cancer spread, and finds that some drugs reduce its expression.

## Contribution

The study reveals that certain systemic therapies can significantly reduce CXCR4 expression and function in neuroendocrine tumor cells.

## Key findings

- Cisplatin significantly reduced CXCR4 mRNA levels and radioligand uptake in some cell lines.
- Temozolomide and Everolimus decreased CXCR4 mRNA and protein levels but did not affect radioligand uptake.
- These findings suggest that drug-induced CXCR4 reduction could influence future targeted therapies.

## Abstract

As neuroendocrine neoplasms (NEN) undergo increasing dedifferentiation, CXC chemokine receptor type 4 (CXCR4) becomes upregulated. Higher levels of CXCR4 are associated with invasive growth, metastasis formation, and poor prognosis. CXCR4 is considered a potential diagnostic biomarker and a promising target for precision therapies — e.g., endoradiotherapeutic approaches, monoclonal antibodies, or small-molecule inhibitors. A variety of systemic therapies are used to treat metastatic NEN, which may modulate CXCR4 expression and potentially influence the efficacy of future CXCR4-targeted strategies. In the NEN cell lines BON-1, QGP-1, and MS-18, we applied cisplatin, etoposide, streptozotocin, 5-fluorouracil, temozolomide, and everolimus- all systemic agents used in highly proliferative NEN. Following incubation, CXCR4 expression was quantified by qRT-PCR, Western blot, and immunohistochemistry. The functional receptor activity was determined by measuring uptake of the radioligand [68Ga]Pentixafor. Cisplatin induced a significant reduction in CXCR4 mRNA levels in BON-1 and QGP-1 cells (p < 0.05) and decreased radioligand uptake in QGP-1 and MS-18. Etoposide, 5-FU, and streptozotocin had no significant impact on CXCR4 expression or uptake activity. Temozolomide and Everolimus markedly diminished both CXCR4 mRNA and protein levels with no significant impact on radioligand uptake. In high-grade NEN cell lines, Cisplatin, Everolimus, and Temozolomide substantially diminish CXCR4 expression, with Cisplatin significantly decreasing CXCR4-targeted radioligand uptake. These findings might have an impact on the optimal therapy sequence and patient selection for future CXCR4-targeted approaches. Further, the decreased CXCR4 expression could represent a new mechanism of action of the established drugs Cisplatin, Temozolomide, and Everolimus.

The online version contains supplementary material available at 10.1038/s41598-026-37026-8.