Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

Conforti, Fabio; Zhang, Xu; Rao, Guanhua; Pas, Tommaso De; Yonemori, Yoko; Rodriguez, José Antonio; McCutcheon, Justine N.; Rahhal, Raneen; Alberobello, Anna Teresa; Wang, Yisong; Zhang, Yu Wen; Guha, Udayan; Giaccone, Giuseppe

doi:10.1158/0008-5472.can-17-1323

Cited by 35 publications

(21 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is unknown if limiting XPO1 results in RB accumulation due to decreased export from the nucleus or if other mechanisms are instrumental in elevating RB. A similar increase of nuclear p53 in thymic epithelial tumors was apparent following selinexor treatment [ 44 ]. The increase in wt RB was coincident with a decrease in cyclin A, a direct E2F/RB target, and cyclin B.…”

Section: Discussionmentioning

confidence: 68%

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

et al. 2018

View full text Add to dashboard Cite

Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies.

show abstract

Section: Discussionmentioning

confidence: 68%

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The diagram was created using the jvenn web tool [208] In several of these studies, the potential prognostic significance of XPO1 expression has been evaluated. Higher XPO1 expression was associated with poorer patient prognosis in patients with ovarian tumors [90] , pancreatic tumors [94] , esophageal tumors [92] , gliomas [84,85] , thymic epithelial tumors [89] , and breast tumors [96] . In contrast, high XPO1 expression was related to better prognosis in osteosarcoma patients [98] .…”

Section: Altered Xpo1 Expression In Human Tumorsmentioning

confidence: 99%

“…The expression level of XPO1 at either the mRNA or protein level has been analyzed in many different cancer types. As summarized in Table 1, XPO1 is frequently overexpressed in tumor samples with respect to the corresponding normal tissue samples [80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] . In fact, XPO1 overexpression was observed in all solid tumor types and hematologic malignances examined, with the exception of liver cancer [91] .…”

Section: Altered Xpo1 Expression In Human Tumorsmentioning

confidence: 99%

“…SINEs were developed in 2012 using structure-assisted relationship methodology combined with a novel computational approach termed consensus-induced fit docking [136,137] , a strategy that relied crucially on the recently solved structures of NES-bound XPO1. The Tables 3 and 4, SINE compounds have been extensively tested in preclinical models of many different hematological malignancies [80,82,83,100,101, and solid tumors [89,95,97, . In these models, SINEs have demonstrated potent in vitro and in vivo activity against cancer cells (including growth inhibition, induction of apoptosis, and cell cycle arrest), with only minor toxic effects on normal cells.…”

Section: Development and Preclinical Evaluation Of Selective Inhibitomentioning

confidence: 99%

See 1 more Smart Citation

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

View full text Add to dashboard Cite

Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

show abstract

“…These compounds show low nanomolar IC 50s against cancer cells and have normal cell sparing properties. The anti-tumor activity of these compounds either alone or in combination with respective standard of care therapeutics have been documented in prostate cancer, lung cancer, breast cancer, glioblastoma, colon cancer, renal cell carcinoma, hepatocellular carcinoma, kidney cancer, thymic cancer, non-Hodgkin’s lymphoma, CLL, AML, ALL and others [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. The lead compound selinexor is fairly well tolerated and has been shown to suppress tumor growth in xenograft models (when given at ~15 mg/kg every other day for three weeks schedule).…”

Section: Chemical Inhibition Of Nuclear Exporter Function In Cancementioning

confidence: 99%

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Muqbil

Azmi

Mohammad

2018

Cancers

View full text Add to dashboard Cite

Pancreatic cancer is a deadly disease that is resistant to most available therapeutics. Pancreatic cancer to date has no effective drugs that could enhance the survival of patients once their disease has metastasized. There is a need for the identification of novel actionable drug targets in this unusually recalcitrant cancer. Nuclear protein transport is an important mechanism that regulates the function of several tumor suppressor proteins (TSPs) in a compartmentalization-dependent manner. High expression of the nuclear exporter chromosome maintenance region 1 (CRM1) or exportin 1 (XPO1), a common feature of several cancers including pancreatic cancer, results in excessive export of critical TSPs to the incorrect cellular compartment, leading to their functional inactivation. Small molecule inhibitors of XPO1 can block this export, retaining very important and functional TSPs in the nucleus and leading to the effective killing of the cancer cells. This review highlights the current knowledge on the role of XPO1 in pancreatic cancer and how this serves as a unique and clinically viable target in this devastating and by far incurable cancer.

show abstract

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

Cited by 35 publications

References 38 publications

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Contact Info

Product

Resources

About