Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin

Cesare, Michelandrea De; Cominetti, Denis; Doldi, Valentina; Lopergolo, Alessia; Deraco, Marcello; Gandellini, Paolo; Friedlander, Sharon; Landesman, Yosef; Kauffman, Michael; Shacham, Sharon; Pennati, Marzia; Zaffaroni, Nadia

doi:10.18632/oncotarget.3761

Cited by 38 publications

(32 citation statements)

References 41 publications

(62 reference statements)

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“…p53 is an important cargo of CRM1 (45,46), but clearly for EWS, it is not a biomarker to predict response to KPT-330. This appears to be the same in other studies (18,19,(47)(48)(49)(50)(51). For example, in one of our previous studies, we showed that p73 plays an important role in mediating cell cycle EWS cells have very few somatic mutations highlighting the crucial role of the EWS fusion gene and its downstream pathways in the pathogenesis of the disease (3).…”

Section: Discussionsupporting

confidence: 85%

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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Section: Discussionsupporting

confidence: 85%

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

et al. 2016

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“…The human mycoplasma-free DMPM cell lines MesoII, STO, MP115, MP4, and MP8 were established in our laboratory [11–13]. All cells were cultured in DMEM F-12 medium (Lonza, Milano s.r.l., Treviglio, Italy) supplemented with 10% fetal bovine serum in a 37 °C humidified 5% CO 2 incubator.…”

Section: Methodsmentioning

confidence: 99%

“…Based on the knowledge that several receptor tyrosine kinases (RTKs) are validated targets of miR-34a [8] and our previous results indicating that activation of downstream RTK signaling, in terms of phosphorylation/overexpression of extracellular signal regulated kinase ½ (ERK1/2), AKT, and mTOR, is present in a considerable fraction of DMPM clinical specimens [10], we proposed to investigate the possible relevance of miR-34a in the disease, with the final aim to develop novel therapeutic strategies. Here, we report that miR-34a is down-regulated in DMPM clinical specimens and demonstrate that miR-34a replacement in a unique collection of in-house-developed human DMPM experimental models [11–13] inhibits cell proliferation and invasion and impairs tumor growth formation in SCID mice, mainly as a consequence of c-MET and AXL inhibition. These findings identified miR-34a-AXL and -c-MET axes as promising therapeutic targets for DMPM.…”

Section: Introductionmentioning

confidence: 93%

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

et al. 2017

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BackgroundThe value of microRNAs (miRNAs) as novel targets for cancer therapy is now widely recognized. However, no information is currently available on the expression/functional role of miRNAs in diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional treatments, for which the development of new therapeutic strategies is urgently needed. Here, we evaluated the expression and biological effects of miR-34a—one of the most widely deregulated miRNAs in cancer and for which a lipid-formulated mimic is already clinically available—in a large cohort of DMPM clinical samples and a unique collection of in house-developed preclinical models, with the aim to assess the potential of a miR-34a-based approach for disease treatment.MethodsmiR-34a expression was determined by qRT-PCR in 45 DMPM and 7 normal peritoneum specimens as well as in 5 DMPM cell lines. Following transfection with miR-34a mimic, the effects on DMPM cell phenotype, in terms of proliferative potential, apoptotic rate, invasion ability, and cell cycle distribution, were assessed. In addition, three subcutaneous and orthotopic DMPM xenograft models were used to examine the effect of miR-34a on tumorigenicity. The expression of miRNA targets and the activation status of relevant pathways were investigated by western blot.ResultsmiR-34a was found to be down-regulated in DMPM clinical specimens and cell lines compared to normal peritoneal samples. miR-34a reconstitution in DMPM cells significantly inhibited proliferation and tumorigenicity, induced an apoptotic response, and declined invasion ability, mainly through the down-regulation of c-MET and AXL and the interference with the activation of downstream signaling. Interestingly, a persistent activation of ERK1/2 and AKT in miR-34a-reconstituted cells was found to counteract the antiproliferative and proapoptotic effects of miRNA, yet not affecting its anti-invasive activity.ConclusionsOur preclinical data showing impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of RTK downstream signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0387-6) contains supplementary material, which is available to authorized users.

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“…As a predominantly cytoplasmic protein, survivin is exported to the cytoplasm through an exclusively XPO1-dependent pathway (5). In malignant peritoneal mesothelioma, survivin was shown to rely on XPO1 to be shuttled into the cytoplasm for its antiapoptotic function (23). While expression of survivin has been shown to be regulated by nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) in breast cancer (24), activated NFkB pathway has also been shown to contribute to malignant progression of adult T-cell leukemia (ATL) through survivin (25).…”

Section: Introductionmentioning

confidence: 99%

Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

Nair

Musi

Schwartz

2017

Clinical Cancer Research

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Purpose: Selinexor, a small molecule that inhibits nuclear export protein XPO1, has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few, and hence the need to identify novel targets and strategic therapies is of utmost importance.Experimental Design: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated.Results: Selinexor induced IkB nuclear localization as a single agent, and the effect was enhanced by stabilization of IkB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IkB in the nucleus resulted in inhibition of NFkB and transcriptional suppression of the critical antiapoptotic protein, survivin. Treatment of carfilzomib followed by selinexor caused selinexor-sensitive and selinexor-resistant cell lines to be more sensitive to selinexor as determined by an increase in apoptosis. This was successfully demonstrated in the MPNST xenograft model with enhanced tumor suppression.Conclusions: The subcellular distributions of IkB and NFkB are indicative of carcinogenesis. Inhibition of XPO1 results in intranuclear retention of IkB, which inhibits NFkB and thereby provides a novel mechanism for drug therapy in sarcoma. This effect can be further enhanced in relatively selinexor-resistant sarcoma cell lines by pretreatment with the proteasome inhibitor carfilzomib. Because of these results, a human clinical trial with selinexor in combination with a proteasome inhibitor is planned for the treatment of sarcoma.

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Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin

Cited by 38 publications

References 41 publications

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

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

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

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