Tetraploidization increases sensitivity to Aurora B kinase inhibition

Marxer, Miriam; Foucar, Charles; Man, Wingyu; Chen, Yu; Tang, Hoi; Poon, Randy Y. C.

doi:10.4161/cc.20947

Cited by 20 publications

(21 citation statements)

References 30 publications

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“…49 Investigations of small molecule Aurora B therapeutics are currently on the way, as several Aurora B protein inhibitors are entering clinical trials. [54][55][56][57][58][59] However, all the research so far were all focused on the inhibition of Aurora B activity. When testing CaM inhibitors on human adenocarcinoma cell growth, only calmidazolium displayed highly potent inhibitory activity (K d = 46 nM, Fig.…”

Section: Discussionmentioning

confidence: 99%

Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis

et al. 2013

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“…Defective apoptotic pathways, facilitating the survival of polyploid cells, may also influence their sensitivity to cytotoxic and targeted agents. Recently, tetraploid cells have been shown to have an increased sensitivity to Aurora B inhibition (28), presenting a potential therapeutic approach for these tumors. However, we were unable to show increased sensitivity of the 533533-R1 line or FACS-sorted hyperpentaploid cells to an Aurora B-specific inhibitor (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells inCCNE1-Amplified Ovarian Cancer

Etemadmoghadam

Au-Yeung

Wall

et al. 2013

Clinical Cancer Research

100

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Purpose: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in highgrade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance.Experimental Design: We examined the effect of CDK2 suppression using RNA interference and smallmolecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 amplification and polyploidy using data from primary tumors.Results: We validate CDK2 as a therapeutic target in CCNE1-amplified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 amplification.Conclusions: These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy.

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“…Tetraploid cells are intrinsically resistant against DNA damaging agents (9), yet are more susceptible to a variety of agents including inhibitors of checkpoint kinase 1 (19), Aurora kinase B (20), and mitotic kinesins (21,22). Nonetheless, such agents can perturb normal mitoses and mitotic checkpoints, casting doubts on their potential utility as chemopreventive agents.…”

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confidence: 99%

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

Lissa

Senovilla

Rello-Varona

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc Min/+ mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.

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Tetraploidization increases sensitivity to Aurora B kinase inhibition

Cited by 20 publications

References 30 publications

Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis

Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis

Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells inCCNE1-Amplified Ovarian Cancer

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

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