Anti-tumor efficacy of Selinexor (KPT-330) in gastric cancer is dependent on nuclear accumulation of p53 tumor suppressor

Vinod Vijay Subhash,Praveen C Peethala,Sharon Shacham,H Phillip Koeffler,Win Lwin Thuya,Wei Peng Yong,Foong Ying Wong,Nisha Padmanabhan,Mu Yar Soe,Mei Shi Yeo,Shi Hui Tan,David S P Tan,Lingzhi Wang,Erkan Baloglu,Woei Loon Tan,Patrick Tan

doi:10.1038/s41598-018-30686-1

Abstract

Exportin-1 (XPO1) controls the nucleo-cytoplasmic trafficking of several key growth regulatory and tumor suppressor proteins. Nuclear export blockade through XPO1 inhibition is a target for therapeutic inhibition in many cancers. Studies have suggested XPO1 upregulation as an indicator of poor prognosis in gastric cancer. In the current study, we investigated the anti-tumor efficacy of selective inhibitors of nuclear export (SINE) compounds KPT-185, KTP-276 and clinical stage selinexor (KPT-330) in gastric cancer. XPO1 was found to be overexpressed in gastric cancer as compared to adjacent normal tissues and was correlated with poor survival outcomes. Among the 3 SINE compounds, in vitro targeting of XPO1 with selinexor resulted in greatest potency with significant anti-proliferative effects at nano molar concentrations. XPO1 inhibition by selinexor resulted in nuclear accumulation of p53, causing cell cycle arrest and apoptosis. Also, inhibition of XPO1 lead to the cytoplasmic retention of p21 and suppression of survivin. Orally administered selienxor caused significant inhibition of tumor growth in xenograft models of gastric cancer. Furthermore, combination of selinexor with irinotecan exhibited greater anti-tumor effect compared to individual treatment. Taken together, our study underscores the therapeutic utility of XPO1 targeting in gastric cancer and suggests the potential benefits of XPO1 inhibition in-combination with chemotherapy.

Highlights

Intracellular location of tumor suppressor proteins (TSPs) and growth regulatory proteins (GRPs) is critical to cancer cells for proliferation and survival[1]
Selective inhibitor of nuclear export (SINE) compounds (KPT-185, KPT-276, and KPT-330) were developed based on the fact that Leptomycin B binds to the Cys[528] residue in the cargo-binding groove of XPO1 to restore the function of TSPs in the nucleus, leading them to induce cancer-specific apoptosis[7]
We investigated the therapeutic efficiency of XPO1 inhibition with SINE compounds KPT-185, KPT-276 and KPT-330 in gastric cancer

Summary

Introduction

Intracellular location of tumor suppressor proteins (TSPs) and growth regulatory proteins (GRPs) is critical to cancer cells for proliferation and survival[1]. During malignant transformation or in response to the tumor environment, cancer cells appear to acquire intracellular mechanisms for nuclear exclusion of tumor suppressor proteins[2]. In this regard, therapeutic targeting of the nucleo-cytoplasmic shuttling of macromolecules has emerged as a promising approach in cancer treatment[3]. Selective inhibitor of nuclear export (SINE) compounds (KPT-185, KPT-276, and KPT-330) were developed based on the fact that Leptomycin B binds to the Cys[528] residue in the cargo-binding groove of XPO1 to restore the function of TSPs in the nucleus, leading them to induce cancer-specific apoptosis[7]. The anti-tumor efficacy of KPT330 is characterized using a xenograft model of gastric cancer

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Results

Conclusion