Abstract 225P
Background
Advanced pancreatic neuroendocrine tumors (pNETs) show minimal response to FDA approved therapies suggesting an urgent need for the identification of novel and effective therapeutic targets. Aberrant nuclear protein transport to the cytoplasm, often observed in cancer, causes mislocalization dependent inactivation of critical cellular proteins. The major nuclear exporter exportin-1 (XPO1) has been linked to cancer therapy resistance. Nevertheless, the role of XPO1 in pNET has not been explored. Major pNET growth regulators such as MEN1, DAXX and mTOR are recognized cargo proteins of XPO1 and thus their nucleo-cytoplasmic transport is regulated by XPO1. Here we explored the role of XPO1 in pNET subsistence and therapy resistance.
Methods
We performed immunohistochemistry (IHC) analysis for XPO1 on 145 low grade pNET tumors, 35 normal and established cell lines. The impact of XPO1 inhibitor selinexor and analogs was evaluated in pNET 2D and 3D cultures, xenograft and primary explant cultures.
Results
IHC on TMAs confirmed XPO1 over-expression in pNET tumor tissue. FDA approved and investigational XPO1 inhibitors selinexor and eltanexor suppressed BON-1 and QGP-1 pNET cell line growth at pharmacologically relevant concentrations. Selinexor synergized with everolimus and sunitinib leading to superior pNET cell death (CI<1). Immunofluorescence analysis showed nuclear retention of mTOR and MEN1 as well as perinuclear accumulation of DAXX in BON-1 pNET cell line. Selinexor suppressed phosphorylation of mTOR and its downstream targets P70S6K and RICTOR. We observed significant inhibition of MEN1 targets including suppression of FANCD2 and SMAD3 and activation of p53. Selinexor given at sub-optimal dose of 15 mg/kg twice a week for three weeks suppressed the growth of BON-1 and QGP-1 tumors. An examination of residual tumors showed reduction in mTOR downstream target pS6 and reduced nuclear expression of pAKT. Six day treatment with 300 nM selinexor demonstrated marked reduction in proliferation marker ki67 and nuclear retention of well recognized XPO1 cargo FOXO3a in the explant culture tissue.
Conclusions
Our results indicate that XPO1 could be a novel therapeutic target that warrants further clinical investigations in pNETs.
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute.
Disclosure
All authors have declared no conflicts of interest.