Molecular Basis of Drug Resistance in Aurora Kinases

Girdler, F; Sessa, Fabio; Patercoli, Simona; Villa, Fabrizio; Musacchio, Andrea; Taylor, Stephen S.

doi:10.1016/j.chembiol.2008.04.013

Cited by 107 publications

(113 citation statements)

References 40 publications

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“…This is supported by the finding that the Aurora kinase inhibitor, MLN8054, is equipotent in vitro at concentrations that inhibit both Aurora A and B irrespective of MDR1 or BCRP status (Figure 6b). Recently, Girdler et al 16 reported the identification of several Aurora B kinase domain mutations that emerge during selection of the DNA repair-defective colon carcinoma line, HCT116, in ZM447439. These catalytic domain mutations were also sufficient to render cells resistant to AZD1152 and VX-680 indicating that resistance to these agents can occur independently of MDR.…”

Section: Discussionmentioning

confidence: 99%

“…Direct DNA sequencing of the Aurora B gene in both drugresistant lines confirmed that no mutation had occurred during selection (data not shown) as has been reported for ZM447439-resistant HCT116 variants. 16 We next carried out genome-wide microarray analysis of the parental and drugresistant cells to identify gene expression changes that could be correlated with resistance to AZD1152 HQPA. In the drugresistant SW620 derivative (hereafter referred to as SW620 MDR1/3 ), ABCB1, which encodes MDR1, was the most highly overexpressed gene on the array and was identified by two distinct probe sets (Figure 1a).…”

Section: Generation and Characterization Of Azd1152 Hqpa-resistant Camentioning

confidence: 99%

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Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

et al. 2009

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Section: Discussionmentioning

confidence: 99%

Section: Generation and Characterization Of Azd1152 Hqpa-resistant Camentioning

confidence: 99%

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

et al. 2009

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“…Furthermore, it has been shown that mutations within the Aurora-B gene are generated on drug treatment and this can lead to resistance toward Aurora-B kinase inhibitors, including ZM447439 (46).…”

Section: Discussionmentioning

confidence: 99%

Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells

Kaestner

Stolz²,

Bastians³

2009

Molecular Cancer Therapeutics

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The mitotic Aurora kinases, including Aurora-A and Aurora-B, are attractive novel targets for anticancer therapy, and inhibitory drugs have been developed that are currently undergoing clinical trials. However, the molecular mechanisms how these drugs induce tumor cell death are poorly understood. We have addressed this question by comparing the requirements for an efficient induction of apoptosis in response to MLN8054, a selective inhibitor of Aurora-A, and the selective Aurora-B inhibitor ZM44-7439 in human colon carcinoma cells. By using various isogenic knockout as well as inducible colon carcinoma cell lines, we found that treatment with MLN8054 induces defects in mitotic spindle assembly, which causes a transient spindle checkpoint-dependent mitotic arrest. This cell cycle arrest is not maintained due to the activity of MLN8054 to override the spindle checkpoint. Subsequently, MLN8054-treated cells exit from mitosis and activate a p53-dependent postmitotic G 1 checkpoint, which subsequently induces p21 and Bax, leading to G 1 arrest followed by the induction of apoptosis. In contrast, inhibition of Aurora-B by ZM447439 also interferes with normal chromosome alignment during mitosis and overrides the mitotic spindle checkpoint but allows a subsequent endoreduplication, although ZM447439 potently activates the p53-dependent postmitotic G 1 checkpoint. Moreover, the ZM447439-induced endoreduplication is a prerequisite for the efficiency of the drug. Thus, our results obtained in human colon carcinoma cells indicate that although both Aurora kinase inhibitors are potent inducers of tumor cell death, the pathways leading to the induction of apoptosis in response to these drugs are distinct.

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“…Whereas initial efforts were focused on aurora A, recent data suggest that aurora B is a relevant cancer target (Girdler et al, 2006;Girdler et al, 2008). In addition, the ability of aurora C to drive CPC function suggests the relevance of this protein in specific cell types.…”

Section: Research Articlementioning

confidence: 99%

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

Fernández-Miranda

Trakala

Martı́n³

et al. 2011

Development

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SUMMARYMitosis is controlled by multiple kinases that drive cell cycle progression and prevent chromosome mis-segregation. Aurora kinase B interacts with survivin, borealin and incenp to form the chromosomal passenger complex (CPC), which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. Whereas genetic ablation of survivin, borealin or incenp results in early lethality at the morula stage, we show here that aurora B is dispensable for CPC function during early cell divisions and aurora B-null embryos are normally implanted. This is due to a crucial function of aurora C during these early embryonic cycles. Expression of aurora C decreases during late blastocyst stages resulting in post-implantation defects in aurora B-null embryos. These defects correlate with abundant prometaphase figures and apoptotic cell death of the aurora B-deficient inner cell mass. Conditional deletion of aurora B in somatic cells that do not express aurora C results in chromosomal misalignment and lack of chromosome segregation. Re-expression of wild-type, but not kinase-dead, aurora C rescues this defect, suggesting functional overlap between these two kinases. Finally, aurora B-null cells partially arrest in the presence of nocodazole, suggesting that this kinase is not essential for the spindle assembly checkpoint.

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Molecular Basis of Drug Resistance in Aurora Kinases

Cited by 107 publications

References 40 publications

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

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