SFEBES2023 Oral Communications Neuroendocrinology and Pituitary (6 abstracts)
CDC42: a potential therapeutic target of clinically non-functioning pituitary neuroendocrine tumours
Ashutosh Rai 1 , Federica Begalli 1 , Sayka Barry 1 , Thomas Rice 1 , Kesson Magid 1 , Oniz Suleyman 1 , Neil Dorward 2 , Joan Grieve 2 , Angelos Kolias 2 , Danyal Khan 2 , Hani J. J Marcus 2 , Bishan D. Radotra 3 , Rajesh Chhabra 3 , S S. Dhandapani 3 , Manjul Tripathi 3 , Chirag K. Ahuja 3 , Pinaki Dutta 3 & Márta Korbonits 1
1Queen Mary University of London, London, United Kingdom. 2UCL Queen Square Institute of Neurology, London, United Kingdom. 3Postgraduate Institute of Medical Education and Research, Chandigarh, India
Background: There is no effective medical treatment available for non-functioning pituitary neuroendocrine tumours (NF-PitNETs). Recurrence (7-12%) or incomplete resection (30-45%) is a common feature. Thus, finding novel medical therapies to help the management of these tumours would be of great value. By using high-throughput mass spectrometry combined with functional characterisation, we explored novel therapeutic targets for NF-PitNETs.
Methods: Tandem mass tag-based mass spectrometry was performed on 20 frozen tissue samples (non-recurrent (n =15), recurrent (n =5)) from patients with clinically nonfunctioning PitNETs. We used RT-qPCR (n =20) and immunohistochemistry (n =50) to confirm our results. Cell viability, invasion & migration, and wound healing assays were performed in mouse gonadotroph cell lines (αT3-1 and LβT2 cells) and primary human tumour cells from NF-PitNETs.
Results: Proteomic analysis showed upregulation of 31 proteins of the CDC42 signalling pathway members in recurrent NF-PitNETs, and increased CDC42 expression was confirmed by immunohistochemistry compared to normal pituitaries (<0.0001), with the higher expression in recurrent compared to non-recurrent (P=0.02). Proliferative tumours (Trouillas category 1b and 2b) showed increased CDC42 gene and protein expression compared to non-proliferative tumours (1a and 2a) (P=0.04). Significant time- and dose-dependent decrease in cell viability was seen in αT3-1 and LβT2 cells upon treatment with CDC42 pathway inhibitors MBQ-167 (P<0.0001), ML141 (P=0.0005) and FRAX486 (P<0.0001). These agents also showed cytotoxic effect on primary human NF-PitNET cells (n =18) (P<0.0001). Significant inhibition was observed in ML141-treated cells in migration assays (αT3-1, P=0.006; LβT2, P=0.0006), as well as in transwell invasion assays at 24 hrs (αT3-1, P<0.0001; LβT2, P=0.01), and 48 hrs (αT3-1, P=0.01; LβT2, P=0.03).
Conclusion: Our results demonstrate that CDC42 pathway is especially upregulated in recurrent NF-PitNETs. The potent inhibitory effect of ML141 on proliferation, migration and invasion of gonadotroph cell lines and human tumour cells in primary culture points to a therapeutical effect.
Volume 94
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Endocrine Abstracts
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