Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer

Abstract

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.

Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance

“…Interestingly, in a distinct study, selinexor was shown to overcome TKI resistance in a leukemia model [18]. Moreover, a recent study from our lab has demonstrated that XPO1 may act as a promising molecular target in gastric cancer and blocking it using SINE compounds can have therapeutic significance [19]. In alignment to these studies, our RNA seq analysis showed activation of cargo receptor activity and nuclear pore signaling molecules in the resistant thyroid cell line.…”

Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with NUP214 rearrangements

“…In fact, both fusion proteins can bind CRM1 and its co-factor, the small GTPase Ran, and inhibit the nuclear export of NES-containing proteins and RNPs [22,23,25]. Targeted CRM1 inhibition by small molecule antagonists has become an appealing anti-cancer strategy, for both solid and hematologic malignancies [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Leptomycin B (LMB), a fungal metabolite from Streptomyces spp, was the first identified small molecule inhibitor specifically targeting CRM1 [41].…”

Gastric Cancer Heterogeneity and Clinical Outcomes

“… 54 XPO1 overexpression was found to be a therapeutic target in GC and we have found blocking the protein with the small FDA approved molecule selinexor (XPOVIO) influences the expression of a subset of tumor-associated miRNAs. 55 Furthermore, we have found via small RNA sequencing that after XPO1 inhibition with selinexor as well as the second generation inhibitor KPT-8602, miR-7977 ( CWH43 interacting miRNA) is significantly upregulated (fold change 2.22, P = 3.92E-23 and fold change 2.08, P = 5.46E-20) in the early stage diffuse gastric cell line SNU-1 suggestive of the tumor suppressive role of this miRNA. The connection between nuclear export and cancer-specific miRNAs in GC has not been investigated in depth.…”

“…54 XPO1 overexpression was found to be a therapeutic target in GC and we have found blocking the protein with the small FDA approved molecule selinexor (XPO-VIO) influences the expression of a subset of tumor-associated miRNAs. 55 Furthermore, we have found via small RNA sequencing that after XPO1 inhibition with selinexor as well not been investigated in depth. We are working toward not only characterizing this novel interaction but also using this information to uncover novel genes pertinent to GC growth and development.…”