Abstract
Somatostatin analogues (SSA) represent the standard of care for symptom control in patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In addition, SSA exert significant anti-proliferative effects in mid-gut and pancreatic NET (PanNET). In parallel, molecularly targeted therapies (MTT) have been shown to improve progression free survival (PFS) in patients with PanNET. However, due to either primary or acquired resistance to MTT, their impact on overall survival (OS) remains unclear. To date, various hypotheses exist to explain differences in patient responsiveness to SSA and MTT. However, data addressing one of the most pivotal questions, whether combining SSA with novel MTT will result in synergistic or additive efficacy compared to monotherapy, are lacking. The aim of this study is to characterize the interaction, optimal sequence and dosing of SSA-based and molecularly targeted therapies in PanNET. Somatostatin receptor subtypes 1–5 (SSTR) were evaluated in the neuroendocrine cell lines Bon1, QGP1 and Ins-1 via immunoblot and qRT-PCR. The impact of the SSA-analogue lanreotide alone or in combination with the MTT sunitinib, everolimus and regorafenib on intracellular signalling, hormone secretion and cell proliferation was determined in cell lysates and supernatants. In addition, synergistic effects of SSA and MTT in various sequential therapeutic approaches were investigated. SSTR were differently expressed in the examined neuroendocrine tumor cell lines. SSTR modulation via lanreotide moderately influenced proliferation, mainly via modulating AKT and ERK signalling, which was paralleled by decreased chromogranin A (CgA) expression and secretion. Interestingly, MTT treatment with regorafenib upregulated the expression of SSTR-2 and -5, while sunitinib and everolimus did not significantly alter SSTR expression. Cell viability was significantly reduced by all MTT, with regorafenib exerting the most significant effects. However, compared to the marked effects of MTT alone, synergistic effects of combined MTT and lanreotide treatment were only modest and time- and dose-dependent. SSTR are differentially expressed in various NEN cell lines. Their expression is influenced by MTT treatment. Various sequential or simultaneous combinations of lanreotide and MTT did not lead to significant synergistic effects.
Highlights
Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-neuroendocrine tumors (NET)) represent a rare and heterogeneous disease [1, 2]
Based on the low basal expression of SSTR3 and -4 in all cell lines, we focused on SSTR1,2 and -5 in our further experiments
S2 Fig. qRT-PCR triplicates of Bon1 and QGP1 cells treated with lanreotide, regorafenib, everolimus and sunitinib for 24h and 48h
Summary
Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NET) represent a rare and heterogeneous disease [1, 2]. While symptoms frequently occur late, the majority of NET patients are diagnosed with metastatic disease [3, 4]. In case of unresectable and metastatic disease medical treatment has shown to improve the long-term outcome of patients [5]. GEP-NET are characterized by the expression of somatostatin receptors (SSTR). The SSTR2A is exclusively expressed in human tissue and a membrane-bound receptor, whereas SSTR1, 3 and 5 are located intracellularly [7]. Previous data indicated a correlation of SSTR2 expression, differentiation and prognosis in GEP-NET patients [9, 10]
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