Aurora kinases: novel therapy targets in cancers

Tang, Anqun; Gao, Keyu; Chu, Laili; Zhang, Rui; Yang, Jing; Zheng, Junnian

doi:10.18632/oncotarget.14893

Cited by 275 publications

(243 citation statements)

References 158 publications

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“…Together with cell biological evidence that inhibition of AurA compromises mitotic progression, an increased AurA expression profile in cancer supports that AurA is a clinically relevant drug target (48). Pharmaceutical companies have begun to exploit this possibility, bringing numerous targeted inhibitors to the market as anti-cancer drugs, and spurring clinical trials (37,(49)(50)(51)(52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

Navarro-Serer¹,

Childers²,

Hermance³

et al. 2018

Preprint

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The presence of supernumerary centrosomes is prevalent in cancer, where they promote the formation of transient multipolar mitotic spindles. Active clustering of supernumerary centrosomes enables the formation of a functional bipolar spindle that is competent to complete a bipolar division. Disruption of spindle pole clustering in cancer cells promotes multipolar division and generation of non-proliferative daughter cells with compromised viability. Hence molecular pathways required for spindle pole clustering in cells with supernumerary centrosomes, but dispensable in normal cells, are promising therapeutic targets. Here we demonstrate that Aurora A kinase activity is required for spindle pole clustering in cells with extra centrosomes. While cells with two centrosomes are ultimately able to build a bipolar spindle and proceed through a normal cell division in the presence of Aurora A inhibition, cells with supernumerary centrosomes form multipolar and disorganized spindles that are not competent for chromosome segregation. Instead, following a prolonged mitosis, these cells experience catastrophic divisions that result in grossly aneuploid, and non-proliferative daughter cells. Aurora A inhibition in a panel of Acute Myeloid Leukemia cancer cells has a similarly disparate impact on cells with supernumerary centrosomes, suggesting that centrosome number and spindle polarity may serve as predictive biomarkers for response to therapeutic approaches that target Aurora A kinase function.

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Section: Discussionmentioning

confidence: 99%

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

Navarro-Serer¹,

Childers²,

Hermance³

et al. 2018

Preprint

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“…Finally we could show the importance of CDK2 as a master regulator of many kinases and transcription factors such as MYC, AURKB, E2F4 and consequently TP53 and ATM activities ( Figure 4 D ). In particular, AURKB, which directly controls TP53 and ATM activities, appears to be a promising marker of kidney cancer [46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses

Dugourd

Kuppe

Sciacovelli

et al. 2020

Preprint

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Multi-omics datasets can provide molecular insights beyond the sum of individual omics.Diverse tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from nine renal cell carcinoma patients. We used COSMOS to generate novel hypotheses such as the impact of Androgen Receptor on nucleoside metabolism and the influence of the JAK-STAT pathway on propionyl coenzyme A production. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies.

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“…In B-cell acute lymphoblastic leukemia, this axis is considered a pathogenic contributor to high-hyperdiploidy, a common and initiating oncogenic event (Molina et al, 2020). Aurora B kinase itself is a longstanding target in cancer therapy (Helfrich et al, 2016;Tang et al, 2017;Wilkinson et al, 2007). These data highlight the clinical relevance of mitotic chromosome assembly.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Flashner

Swift

Sowash

et al. 2020

Preprint

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Mitotic chromosome assembly is essential for faithful chromosome segregation. Despite their salient role directing interphase chromatin organization, little is known about how transcription factors mediate this process during mitosis. Here, we characterize a mitosis-specific role for transcription factor specificity protein 1 (Sp1). Sp1 localizes to mitotic centromeres and auxininduced rapid Sp1 degradation results in chromosome segregation errors and aberrant mitotic progression. These defects are driven by anomalous mitotic chromosome assembly. Sp1 degradation results in chromosome condensation defects through reduced condensin complex I localization. Sp1 also mediates the localization and activation of Aurora B kinase early in mitosis, which is essential for condensin complex I recruitment. Underscoring the clinical significance of our findings, aberrant Sp1 expression correlates with aneuploidy in several human cancers, including kidney renal papillary cell carcinoma, ovarian serous cystadenocarcinoma, mesothelioma, cholangiocarcinoma, and hepatocellular carcinoma. Our results suggest that Sp1 protects genomic integrity during mitosis by promoting chromosome assembly.

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Aurora kinases: novel therapy targets in cancers

Abstract: ABSTRACT

Cited by 275 publications

References 158 publications

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

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