Abstract 2491: Nuclear exporter protein XPO1 a novel prognostic and therapeutic target in gastric cancer

Abstract

Abstract The high mortality rate associated with Gastric Cancer (GC) indicates the urgent need for actionable therapeutic targets. The nuclear exporter protein exportin 1 (XPO1/CRM1) is the exclusive exporter of many tumor suppressor proteins (TPSs) and growth regulators. XPO1 is often over-expressed in different malignancies leading to aberrant cytoplasmic localization of TSPs and subsequent inactivation. A detailed analysis on the correlation of XPO1 with inflammation-metaplasia-dysplasia-carcinoma sequence progression was performed using immunohistochemistry in 70 GC cases: (a) 10 cases from normal gastric mucosa, (b) 10 cases of stomach with intestinal metaplasia with and without inflammation, (c) 10 cases of mucosa with low-grade dysplasia (d) 10 cases of mucosa with high-grade dysplasia, (e) 10 cases of gastric adenocarcinoma and (f) 20 cases of metastatic gastric carcinoma. A correlation between XPO1 expression, the pathological and clinical features of the disease as well as survival were analyzed. Gastric cancer cell lines were exposed to the Selective Inhibitors of Nuclear Export (SINE) compounds (selinexor, KPT-8602, KPT-185, or the natural agent, leptomycin B (LMB), then analyzed using cytotoxicity and molecular assays. In addition, the activity of selinexor was evaluated in a sub-cutaneous xenograft of gastric cancer cell line NCI-N87. XPO1 served as a prognostic marker for poor outcome as positive staining of XPO1 in GC correlated with aggressive behavior of the disease. Targeting XPO1 using SINE compounds or LMB resulted in inhibition of GC cellular growth (IC50<200 nM), induction of apoptosis and suppression of colony formation (p<0.01). Molecular analysis revealed nuclear retention of several important TSPs, induction of pro-apoptotic proteins and suppression of pro-survival factor Bcl-2. Selinexor given orally at doses of 15 mg/kg twice a week for three weeks caused statistically significant reduction of NCI-N87 tumors in mice (p<0.05). Efficacy studies of SINE compounds in patient derived models of GC are ongoing. Our findings strongly demonstrate the potential of XPO1 to serve not only as a prognostic marker but also as a therapeutic marker in GC that warrants further clinical investigations. Citation Format: Irfana Muqbil, Zaid Mahdi, Rahman Choudhary, Erkan Baloglu, William Senapedis, Yosef Landesman, Sharon Shacham, Michael Kauffman, Steve Kim, Rafic Beydoun, Richard N. Berri, Anthony Shields, Ramzi M. Mohammad, Asfar S. Azmi. Nuclear exporter protein XPO1 a novel prognostic and therapeutic target in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2491.