The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Abstract

Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

Unbiased Assessment of H-STS cells as high-fidelity models for gastro-enteropancreatic neuroendocrine tumor drug mechanism of action analysis

“…Lack of sensitivity to third HDACinhibitor, vorinostat, was also correctly predicted, suggesting that H-STS-based OncoTreat analysis is effective at discriminating sensitivity to drugs with closely-related MoA. Consistent with these results, an independent study in bona fide NeuroEndocrine Tumor (NET) cells, reported higher sensitivity to HDAC inhibitors compared to control cells (5).…”

Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

“…OCT also failed to exert anti-proliferative activity in the most frequently used NET cell lines, which showed SST 2 expression levels lower than observed in human NEN tissues [165]. Overall, the lack of SRL effects might be explained by: (i) low SST 2 expression in BON-1 and other cell lines, (ii) limited similarity of GEP-NET cell lines with a tumor phenotype, and (iii) cancer-associated mutations occurred in cell cultures [170]. This implies a careful extrapolation of results, which encourages a shift to patient-derived cultures and xenografts.…”

Somatostatin receptor radionuclide therapy in neuroendocrine tumors

“…Other approaches to increase the cytotoxicity of PRRT include combining the modality with possible radiosensitizers such as cellular signaling inhibitors, DNA damage inducers and DNA damage repair inhibitors (Spetz et al 2017, Hofving et al 2018, Purohit et al 2018.…”