Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

Amira Mohamed,Jean-Robert Delpero,Diego Ferone,Federica Barbieri,Corinne Gerard,Stephane Garcia,Anne Barlier,Patricia Niccoli,Vincent Moutardier,David Romano,Alexandru Saveanu,Manuela Albertelli,Flora Poizat,Thierry Brue,Catherine Roche,Tullio Florio

doi:10.18632/oncotarget.17008

Abstract

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Highlights

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) is a rare and heterogeneous group of tumors, with recent increased incidence and prevalence [1]
Mutations of multiple endocrine neoplasia type 1 syndrome (MEN1), DAXX/ATRX, phosphatase and tensin homolog (PTEN) or down regulation of their respective proteins have been frequently observed in pancreatic neuroendocrine tumors (pNETs)
We explored the effect of everolimus combined with the somatostatin analogs (SSAs) on chromogranin A (CgA) secretion from the 12 pNETs responsive to everolimus in primary cultures. 72h www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget treatment of cells with 1nM octreotide or 1nM pasireotide alone decreased CgA secretion as previously observed [20] (Figure 4A, 4B), except in one primary culture which do not respond to SSAs

Summary

INTRODUCTION

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) is a rare and heterogeneous group of tumors, with recent increased incidence and prevalence [1]. The SSAs octreotide and lanreotide are currently used to reduce symptoms caused by peptides release in a majority of patients carrying functional GEP-NETs [5] These effects have been credited to their binding to the somatostatin receptor subtype 2 (SST2). SSAs anti-proliferative role has been investigated in PROMID and CLARINET studies Both long acting octreotide and lanreotide significantly prolonged progression free survival (PFS) respectively in patients with well-differentiated metastatic midguts GEPNETs and metastatic pNETs [6, 7]. Combined treatments with drugs targeting PI3K/Akt could improve the anti-proliferative effect of everolimus In this regard, activation of SST2 has been shown to repress PI3K activity by disrupting the interaction between SST2 and the p85 PI3K regulatory subunit in pituitary and pancreatic adenocarcinoma cell lines [17, 18]. The role of PI3K/Akt/ mTOR and the MAPKinase ERK1/2 signaling pathways under these treatments has been monitored

RESULTS

DISCUSSION

DECLARATION OF INTEREST