Abstract 6909: Exportin 1 as a novel therapeutic target in gastroenteropancreatic neuroendocrine tumors

Abstract Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 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 GEP-NETs has not been explored. Major GEP-NETs growth regulators such as MEN1, DAXX and mTOR are recognized cargo proteins of XPO1, which regulates their nucleo-cytoplasmic transport. Here we evaluated the role of XPO1 in pancreatic neuroendocrine tumors (pNET) subsistence and therapy resistance. Methods: We performed immunohistochemistry (IHC) analysis for XPO1 on 145 low-grade pNET tumors, and 35 normal, and established cell lines. Growth inhibition was determined by MTT, colony formation and apoptosis assays. Gene expression was determined using quantitative PCR, and protein expression using western blotting and immunofluorescence (IF) techniques. 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. Selective inhibitors of nuclear export (SINE) selinexor and eltanexor suppressed the growth of BON-1 and QGP-1 cells at pharmacologically relevant concentrations. Both inhibitors significantly reduced the number and the area of the colonies, and were able to induce apoptosis. Western blot analysis revealed significant induction of PARP cleavage. The pNET marker Chromogranin A was found to be reduced in the XPO1 inhibitors treated cells in IF assay. Selinexor synergized with everolimus and sunitinib leading to superior pNET cell deaths (combination index<1). IF analysis showed nuclear retention of mTOR and MEN1, and perinuclear accumulation of DAXX in the BON-1 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 low dose (15 mg/kg), twice a week for three weeks suppressed the growth of BON-1 and QGP-1 tumors in vivo. An examination of residual tumors showed a reduction in mTOR downstream target pS6 and reduced nuclear expression of pAKT. Six-day treatment with 300 nM selinexor demonstrated a marked reduction in the proliferation marker ki67 and nuclear retention of the well-recognized XPO1 cargo FOXO3a in the pNET explant tissue. Conclusions: This is the first study to reveal the therapeutic potential of novel XPO1-targeted agents for the treatment of a GEP-NET in vitro and in vivo. XPO1 could be a novel therapeutic target that warrants further clinical investigations in GEP-NETs. Citation Format: Md. Hafiz Uddin, Husain Y. Khan, Amro Aboukameel, Sahar F. Bannoura, Hugo Jimenez, Grayson Barker, Allan M. Johansen, Khalil Choucair, Sunil Jaiman, Gregory Dyson, Yang Shi, Mohammed N. Al Hallak, Nitin Vaishampayan, Steve Kim, Eliza W. Beal, Miguel Tobon, Herbert Chen, Muhammad W. Saif, Jennifer Beebe-Dimmer, Anthony F. Shields, Ramzi M. Mohammad, Philip A. Philip, Bassel El-Rayes, Boris C. Pasche, Asfar S. Azmi. Exportin 1 as a novel therapeutic target in gastroenteropancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6909.