The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma

Sellin, Mark; Berg, Stephanie; Hagen, Patrick; Zhang, Jiwang

doi:10.1016/j.tranon.2022.101448

Cited by 7 publications

(5 citation statements)

References 195 publications

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“…Schematic of the role of XPO1 in transporting various cargoes from the nucleus to the cytoplasm and the effects of XPO1 inhibition with selinexor [27, 29]. CDK, cyclin‐dependent kinase; cIAP, cellular inhibitor of apoptosis protein; NF‐κB, nuclear factor‐κB; GR, glucocorticoid receptor; IL, interleukin; MCL1, myeloid cell leukaemia sequence 1; PUMA, P53 up‐regulated modulator of apoptosis; Rb, retinoblastoma; TSP, tumour suppressor protein; VEGF, vascular endothelial growth factor; XPO1, exportin‐1.…”

Section: Xpo1 Inhibition—a Novel Target In Multiple Myelomamentioning

confidence: 99%

“…XPO1 has been shown to be overexpressed in MM [29,33,34], and an RNA interference screening analysis found it to be among the most vulnerable potential therapeutic targets in the disease [34]. XPO1 plays a number of key roles of relevance in MM [29] F I G U R E 1 Schematic of the role of XPO1 in transporting various cargoes from the nucleus to the cytoplasm and the effects of XPO1 inhibition with selinexor [27,29]. CDK, cyclin-dependent kinase; cIAP, cellular inhibitor of apoptosis protein; NF-κB, nuclear factor-κB; GR, glucocorticoid receptor; IL, interleukin; MCL1, myeloid cell leukaemia sequence 1; PUMA, P53 up-regulated modulator of apoptosis; Rb, retinoblastoma; TSP, tumour suppressor protein; VEGF, vascular endothelial growth factor; XPO1, exportin-1.…”

Section: Xpo1 Inhibition-a Novel Target In Multiple Myelomamentioning

confidence: 99%

“…The role of XPO1, also known as Chromosome Region Maintenance 1, in normal cells and its potential as an anticancer therapeutic target has been extensively reviewed previously [24][25][26][27][28]. Briefly, XPO1 is responsible for the transport of approximately 220 nuclear proteins to the cytoplasm via nuclear pore complexes [25], including a number of crucial tumour suppressor proteins (TSPs) such as Rb, p53, p21 and p27 [28] (Figure 1).…”

Section: Xpo1 Inhibition-a Novel Target In Multiple Myelomamentioning

confidence: 99%

See 2 more Smart Citations

Selinexor: Targeting a novel pathway in multiple myeloma

Yee

Midha

et al. 2023

eJHaem

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Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin‐1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor‐based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor‐dexamethasone approved in the later‐relapse setting for penta‐refractory patients and selinexor‐bortezomib‐dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor‐based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

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Section: Xpo1 Inhibition—a Novel Target In Multiple Myelomamentioning

confidence: 99%

Section: Xpo1 Inhibition-a Novel Target In Multiple Myelomamentioning

confidence: 99%

Section: Xpo1 Inhibition-a Novel Target In Multiple Myelomamentioning

confidence: 99%

See 1 more Smart Citation

Selinexor: Targeting a novel pathway in multiple myeloma

Yee

Midha

et al. 2023

eJHaem

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“…Overexpression of exportin 1 (XPO1) was observed in many cancers, for example, pancreatic, colorectal, and myeloma. This over expression can lead to increased cytoplasmic localiza tion and degradation of tumour suppressors and cell cy cle-negative regulators, such as p53, RB1, or p21 (Sellin et al, 2022). Similarly, the increased expression of im portin subunit α-1 was associated with enhanced cyto plasmic localization of DNA damage response proteins, such as BRCA1, RAD51, or CHK1, in breast cancer (Alshareeda et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic and Prognostic Profiling of Nucleocytoplasmic Shuttling Genes in Hepatocellular Carcinoma

Herceg,

Janoštiak

2023

Fol. Biol.

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One of the key features of eukaryotic cells is the separation of nuclear and cytoplasmic compartments by a double-layer nuclear envelope. This separation is crucial for timely regulation of gene expression, mRNA biogenesis, cell cycle, and differentiation. Since transcription takes place in the nucleus and the major part of translation in the cytoplasm, proper distribution of biomolecules between these two compartments is ensured by nucleocytoplasmic shuttling proteins – karyopherins. Karyopherins transport biomolecules through nuclear pores bidirectionally in collaboration with Ran GTPases and utilize GTP as the source of energy. Different karyopherins transport different cargo molecules that play important roles in the regulation of cell physiology. In cancer cells, this nucleocytoplasmic transport is significantly dysregulated to support increased demands for the import of cell cycle-promoting biomolecules and export of cell cycle inhibitors and mRNAs. Here, we analysed genomic, transcriptomic and proteomic data from published datasets to comprehensively profile karyopherin genes in hepatocellular carcinoma. We have found out that expression of multiple karyopherin genes is increased in hepatocellular carcinoma in comparison to the normal liver, with importin subunit α-1, exportin 2, importin subunit β-1 and importin 9 being the most over-expressed. Moreover, we have found that increased expression of these genes is associated with higher neoplasm grade as well as significantly worse overall survival of liver cancer patients. Taken together, our bioinformatic data-mining analysis provides a comprehensive genomic and transcriptomic landscape of karyopherins in hepatocellular carcinoma and identifies potential members that could be targeted in order to develop new treatment regimens.

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“…Selinexor can help in improving the drug sensitivity of resistant cells by resorting the function of these proteins and by facilitating the expression of DNA-damage repair proteins [ 20 ]. Selinexor can lead to the nuclear accumulation of p53, which leads to accelerating myeloma cell death [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Selinexor in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with del17p and Other High-Risk Abnormalities (A Retrospective Single-Center Study)

Ehsan,

Robinson,

Voorhees

et al. 2024

Life

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Selinexor (Seli) is a first-in-class, oral selective inhibitor of the nuclear export protein, exportin-1 (XPO1). Seli exhibits its antitumor effect through the blockage of XPO1, which increases nuclear retention of tumor suppressor proteins (TSPs), including p53, thereby limiting the translation of oncogenes, triggering cell cycle arrest and the death of malignant cells. Multiple Myeloma (MM) patients with del17p are deficient in TP53 and have a particularly poor prognosis. Given its unique mechanism of action, we investigated whether Seli has increased efficacy in RRMM patients with del17p compared to other high-risk cytogenetics (OHRC). This is an IRB-approved observational study of RRMM patients with high-risk cytogenetics (del17p, t (4;14), t (14;16) or gain 1q) or standard-risk cytogenetics treated at the Levine Cancer Institute (LCI) with a Seli-based regimen between January 2019 and December 2022. Time-to-event endpoints (PFS, OS) were evaluated using Kaplan–Meier (KM) methods. Log-rank tests compared time-to-event endpoints between cohorts [del17p vs. OHRC vs. standard risk]. We identified 40 RRMM patients with high-risk cytogenetics, including 16 patients with del17p and 24 patients with OHRC, as well as 20 with standard-risk cytogenetics. The median age was 62.5 vs. 69 vs. 65.5 years (del17p group vs. OHRC vs. standard risk). The median prior line of therapies was five (range: 3–16) with similar rates of prior autologous stem cell transplant in all arms (68.8% vs. 62.5% vs. 70.0%). The most frequently used regimens were Seli–Pomalidomide–dexamethasone(dex) or Seli–Carfilzomib–dex (Seli-Kd) in the del17p group and Seli-Kd in the OHRC and standard-risk groups. The median time to start the Seli-based regimen after initial MM diagnosis was 5.6 years for the del17p group, 4.1 years in OHRC, and 4.8 years in the standard-risk group. The median follow-up time after the start of the Seli-based regimen was 10.5 months (mos) in the del17p group, 8.4 mos in OHRC, and 10.3 mos in the standard-risk group. In the del17p group, 50% had an objective response, 41.7% in the OHRC, and 35% in the standard-risk group (p = 0.71). Depth of response was also similar across the arms (12.5% vs. 12.5% vs. 10.0% VGPR p = 0.99). The median OS was 10.9 mos in the del17p group, 10.3 mos in the OHRC, and 10.3 mos in the standard-risk group (p = 0.92). The median OS was 15.5 mos for patients who received Seli as a bridging therapy versus 9 mos for Seli use for other reasons rather than as a bridge. Overall, Seli-based regimens showed promising responses even in this heavily pretreated population. Our analysis suggests that Seli-based regimens lead to similar outcomes among RRMM patients with del17p, OHRC, and standard-risk cytogenetics. This contrasts with previously reported outcomes using combinations of novel therapies in this population, where the del17p patients often have a poorer prognosis. Interestingly, our data suggest that Seli is a particularly effective bridging modality for patients preparing for CAR-T cell therapies in our population. Further investigation into this population is warranted, including in earlier lines of therapy, in hopes of seeing a more durable response.

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The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma

Cited by 7 publications

References 195 publications

Selinexor: Targeting a novel pathway in multiple myeloma

Selinexor: Targeting a novel pathway in multiple myeloma

Diagnostic and Prognostic Profiling of Nucleocytoplasmic Shuttling Genes in Hepatocellular Carcinoma

Efficacy of Selinexor in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with del17p and Other High-Risk Abnormalities (A Retrospective Single-Center Study)

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