Aurora Kinases as Therapeutic Targets in Multiple Myeloma.

Reiman, Tony; Evans, Robert P.; Naber, Claudia; Steffler, Tara; Perry, Troy; Maxwell, Christopher A.; Chau, Heidi; Belch, Andrew R.; Pilarski, Linda M.

doi:10.1182/blood.v108.11.847.847

Cited by 3 publications

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“…Activated AURKA successively phosphorylating various centrosomal proteins, functions in centrosome maturation and mitotic spindle formation. The AURKA gene is usually overexpressed in cancer including MM [ 61 , 62 ] and its amplification results in chromosome segregation anomalies related to malignant transformation both in vitro and in vivo [ 60 , 63 ]. Moreover, the upregulation of AURKA inclined chemoresistance in breast cancer and ovarian cancer cells [ 16 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Özenver

Abdelfatah

Klinger³

et al. 2020

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SummaryMultiple myeloma (MM) is a devastating disease with low survival rates worldwide. The mean lifetime of patients may be extendable with new drug alternatives. Aurora A kinase (AURKA) is crucial in oncogenesis, because its overexpression or amplification may incline the development of various types of cancer, including MM. Therefore, inhibitors of AURKA are innovative and promising targets. Natural compounds always represented a valuable resource for anticancer drug development. In the present study, based on virtual drug screening of more than 48,000 natural compounds, the antibiotic deschloro-chlorotricin (DCCT) has been identified to bind to AURKA with even higher binding affinity (free bindung energy: −12.25 kcal/mol) than the known AURKA inhibitor, alisertib (free binding energy: −11.25 kcal/mol). The in silico studies have been verified in vitro by using microscale thermophoresis. DCCT inhibited MM cell lines (KMS-11, L-363, RPMI-8226, MOLP-8, OPM-2, NCI-H929) with IC50 values in a range from 0.01 to 0.12 μM. Furthermore, DCCT downregulated AURKA protein expression, induced G2/M cell cycle arrest and disturbed the cellular microtubule network as determined by Western blotting, flow cytometry, and fluorescence microscopy. Thus, DCCT may be a promising lead structure for further derivatization and the development of specific AURKA inhibitors in MM therapy.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Özenver

Abdelfatah

Klinger³

et al. 2020

Invest New Drugs

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The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma

et al. 2007

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SummaryAurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti‐myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152‐induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti‐myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138+ BM plasma cells from myeloma patients but also, as expected, was toxic to CD138− marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152‐inhibited tumour growth at well‐tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM.

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The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition

Chng

Braggio

Mulligan

et al. 2008

Blood

108

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Centrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression-based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy II) or novel agents (bortezomib). Tumors with high CI overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G 2 -M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis. IntroductionCentrosomes are cellular microtubule-organizing centers whose normal function is crucial for chromosome segregation and cytokinesis during mitosis. 1 Centrosome amplification has been detected in a broad range of solid tumors 2-7 and more recently in leukemia 8,9 and lymphoma. 10-12 Previously, we and others have shown that centrosome amplification is common in multiple myeloma (MM) and is already present in monoclonal gammopathy of undetermined significance (MGUS), suggesting an early role in myelomagenesis. 13,14 In addition, we derived a gene expression-based centrosome index (CI) that correlated closely with centrosome amplification detected by immunofluorescence. We also showed in a heterogeneously treated and relatively small cohort of patients that the CI is an independent prognostic factor. 13 In the current study, we wanted to validate the prognostic importance of the CI in large cohorts of homogenously treated patients entered into clinical trials and study the differences in the gene expression profiles (GEP) of patients with high and low CI in order to understand the underlying biological difference and possibly identify therapeutic targets. Methods PatientsGroup 1: University of Arkansas (UAMS) patients treated with total therapy II. These are newly diagnosed patients entered into total therapy II studies (n ϭ 351). These patients have GEP performed on CD138 ϩ selected plasma cells (PCs) from pretreatment bone marrows (BMs) using the Affymetrix U133plus 2.0 chip (Affymetrix, Santa Clara, CA). The GEP data of these patients have been published. 15 (These data are available from the National Institutes of Health Gene Expression Omnibus, http:// www.ncbi.nlm.nih.gov/geo/, under accession #GSE2658.) These patients were assigned Translocations and Cyclin (TC) class, a gene expressionbased proliferation index (PI), and a recently pu...

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Aurora Kinases as Therapeutic Targets in Multiple Myeloma.

Cited by 3 publications

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Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma

The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition

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