KPT-330 has antitumour activity against non-small cell lung cancer

Sun, Haibo; Hattori, Norimichi; Chien, Wenwen; Sun, Qiao-Yang; Sudo, Makoto; E-Ling, G L; Ding, Ling-Wen; Lim, Su Lin; Shacham, Sharon; Kauffman, Michael; Nakamaki, Tsuyoshi; Koeffler, H. Phillip

doi:10.1038/bjc.2014.260

Cited by 59 publications

(65 citation statements)

References 52 publications

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“…The use of the highly selective p53 inhibitor Pifithrin-alpha (PFT-a; ref. 27) suppressed phosphorylated-ERK1/2 expression (Fig. 3C), consistently increased Bcl-xL expression (Fig.…”

Section: Sine Compounds Induce Apoptosis Through P53-dependent and Inmentioning

confidence: 86%

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Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Chen

Camacho

Silvers

et al. 2017

Clinical Cancer Research

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Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexortreated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer.

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“…The use of the highly selective p53 inhibitor Pifithrin-alpha (PFT-a; ref. 27) suppressed phosphorylated-ERK1/2 expression (Fig. 3C), consistently increased Bcl-xL expression (Fig.…”

Section: Sine Compounds Induce Apoptosis Through P53-dependent and Inmentioning

confidence: 86%

“…An ester moiety on KPT-185 precludes its oral bioavailability and conscripts it to in vitro use (21), while an amide moiety on KPT-330 is associated with excellent bioavailability in all species tested. Both SINE compounds have demonstrated antitumor activity in a number of different cancer types (22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Chen

Camacho

Silvers

et al. 2017

Clinical Cancer Research

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“…Interestingly, XPO1 inhibition also displays a cytotoxic activity in a TP53 mutated lung cancer cell line. In this case, the activity of SINEs seems dependent on TP73, a member of the TP53 family, that is also involved in DNA damageinduced cell-cycle arrest and apoptosis and regulates TP53-dependent genes in TP53-deficient cells (50).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

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“…CRM1 is upregulated in several types of cancer, and its overexpression correlates with a poor prognosis (11,(13)(14)(15)(16)(17). Importantly, CRM1 inhibition by the potent small-molecule selective inhibitor of nuclear export (SINE), KPT-330, has been suggested as a promising therapeutic option for a number of cancer types (18)(19)(20)(21)(22)(23). In this study, we characterized the biologic significance of CRM1 in the context of EWS and determined the therapeutic merit of CRM1 inhibition for this malignancy.…”

Section: Introductionmentioning

confidence: 99%

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

et al. 2016

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Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo. Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9);

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KPT-330 has antitumour activity against non-small cell lung cancer

Cited by 59 publications

References 52 publications

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

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