Upregulation of SSTR2 expression and radioligand binding of [18F]SiTATE in neuroendocrine tumour cells with combined inhibition of class I HDACs and LSD1.

Abstract

Introduction: Peptide receptor radionuclide therapy (PRRT) is a highly effective, targeted treatment option in advanced neuroendocrine tumours (NETs). However, NET patients expressing low levels of Somatostatin receptor type (SSTR)2 do not benefit from this powerful tool. Recently, several preclinical studies have revealed that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 and enhance somatostatin ligand binding to tumour cells. In this preclinical study, we explored the effects of single and combined treatment of NET cells with the class I HDAC inhibitor entinostat and the lysine-specific demethylase 1 (LSD1) inhibitor CC-90011, on cell viability, SSTR2 expression and radioligand binding.

Methods: The human NET cell lines BON1, NCI-H727, and QGP1 were treated with entinostat, CC-90011 or a combination of both. Cell viability was measured with a cell viability assay. SSTR2 expression was assessed by quantitative PCR, Western blot analysis, and immunohistochemistry. [18F]SiTATE uptake was investigated by a radioligand binding assay.

Results: Treatment of NET cells with entinostat, CC-90011 and especially with the combination of both reduced tumour cell viability and strongly induced SSTR2 expression resulting in potently enhanced radioligand binding of [18F]SiTATE.

Conclusion: Combined inhibition of class I HDACs and LSD1 potently increases SSTR2 expression and consequently radioligand binding and might thus be a putative strategy to improve the outcome of PRRT therapy in patients with NETs.