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

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.

Association of XPO1 Overexpression with NF-κB and Ki67 in Colorectal Cancer

“…Our previous study concerned of p53, reported that the XPO1 positivity was associated with loss of p53 expression in CRC tumors with lymph node metastasis (Aladhraei et al, 2019). In the current study, we noticed a significant apparent of XPO1 overexpression in CRC tumor cells compared to the adjacent normal epithelium as it was reported in many other types of cancers such as esophageal (van der Watt et al, 2014), gastric (Subhash et al, 2018), lung (Gao et al, 2015), and ovarian (Noske et al, 2008) cancers, as well as leukemic cells (Kojima et al, 2013). The overexpression of XPO1 within the tumor cells may reflect its abundance and suggests a gain-of-function or oncogenic activity in line of further CRC pathogenesis (Conforti et al, 2015).…”

“…The above results fall in-line with the published data about the KPT-330 ability to sequester the cargoes such as tumor suppressor proteins within the nucleus and leads to cell cycle arrest and proliferation inhibition. The anti-proliferative effect of XPO1 inhibitors were reported in different types of cancer cell lines such as pancreatic cells (Azmi et al, 2017), liver cells (Zheng et al, 2014), prostate cells (Gravina et al, 2015), and gastric cells (Subhash et al, 2018) as well as in colon cancer cell lines (Draetta et al, 2011;Niu et al, 2015). In conclusion, an apparent of XPO1 overexpression in CRC tumor cells compared to the adjacent normal epithelium as well as the association of XPO1 overexpression with advance tumor stages, tumor differentiation and high Ki67 expression may reflect its potential involvement in CRC pathogenesis which can be inhibited by KTP-330.…”

Targeting p53 in chronic lymphocytic leukemia

“…Although the anti-tumoral activity of XPO1 inhibitors is not fully understood, a recent study has shown that the XPO1 inhibitor selinexor conceivably exerts its function by reducing the p53 export out of the nucleus, thus enhancing p53 nuclear retention (Figure 4) [92]. This hypothesis has been also corroborated by the fact that selinexor upregulates the transcription of p53 target genes coding for anti-apoptotic proteins and for proteins that lead to cell cycle arrest such as p21 [94].…”

“…However, cancer cells may progressively acquire intracellular mechanisms for exclusion from the nucleus of tumor suppressor proteins [7]. Remarkably, a fraction of CLL carries mutations of XPO1, that are known to enhance p53 export from the nucleus to the cytoplasm [94]. Inhibiting XPO1, eg with Selinexor, may restore p53 localization to the nucleus and normal function.…”

“…Activation of normal p53 function might also be achieved with non-genotoxic compounds that target and inhibit MDM2, thus stabilizing p53 and activating its transcriptional activity to promote apoptosis. Inhibition of XPO1 and MDM2 might be a strategy at least in cases with monoallelic deletion or monoallelic frameshift or nonsense mutations in which one p53 allele is fully functional [91,94]. In fact, inhibition of XPO1 or MDM2, by different mechanisms, might lead to an increase of the nuclear concentration of wild type p53 derived from the residual normal allele.…”