Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death

Ratushny, Vladimir; Pathak, Harsh B.; Beeharry, Neil; Tikhmyanova, Nadezhda; Xiao, Fang; Li, Tianyu; Litwin, Samuel; Connolly, Denise C.; Yen, Tim J.; Weiner, Louis M.; Godwin, Andrew K.; Golemis, Erica A.

doi:10.1038/onc.2011.314

Cited by 28 publications

(20 citation statements)

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“…The finding that AURKA inhibition in cultured cells and alisertib and paclitaxel treatment of EOC xenografts results in decreased SRC activation suggests another potentially interesting signaling node for dual therapeutic targeting. Previous work (48) demonstrated the capacity for AURKA and SRC interaction and cross phosphorylation in vitro , and the combination of Aurora kinase inhibitors with dasatinib potentiated EOC cell death. Hence, further studies evaluating the combined inhibition of AURKA and SRC may be of clinical interest.…”

Section: Discussionmentioning

confidence: 93%

“…The significantly decreased levels of SRC activation observed in conjunction with pharmacologic or genetic inhibition of AURKA are likely to directly contribute to the observed loss of cellular attachment capacity and motility. Notably, we previously showed that combination of the SRC family inhibitor dasatinib and Aurora kinase inhibitors results in cellular attachment defects that contribute to the specific elimination of cells undergoing dysregulated mitosis and polyploidy (48). The loss of cellular motilty and adhesion may also prevent ovarian carcinoma cells from attaching at secondary sites in the peritoneal cavity, a process critical to ovarian cancer dissemination (49).…”

Section: Discussionmentioning

confidence: 99%

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Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion

Xiao

Bickel

et al. 2013

Oncogene

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Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacologic or RNAi-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRCY416). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared to either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion

Xiao

Bickel

et al. 2013

Oncogene

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“…Subsequent direct testing of pharmacological inhibitors of SRC and Aurora kinases was strongly synergistic in multiple ovarian epithelial carcinoma cell lines, and potently killed cells entering mitosis [79] via interference with a post mitotic reattachment, and selective removal of aneuploid cell populations. Inhibition of SRC with dasatinib has already been shown to yield therapeutic benefit in SCCHN in treatment of cetuximab-resistant tumors.…”

Section: Concepts For Future Trials Of Combination Strategies Involvimentioning

confidence: 99%

Aurora kinases in head and neck cancer

Mehra¹,

Serebriiskii²,

Burtness³

et al. 2013

The Lancet Oncology

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Summary Controlled activation of the Aurora kinases regulates mitotic progression in normal cells. Overexpression and hyperactivation of the Aurora-A and -B kinases play a leading role in tumorigenesis, inducing aneuploidy and genomic instability. In squamous cell carcinomas of the head and neck (SCCHN), overexpression of Aurora-A is associated with decreased survival, and reduction of Aurora-A and -B expression inhibits SCCHN cell growth and increases apoptosis. In this article, we provide a basic overview of the biological functions of Aurora kinases in normal cells and in cancer, and review both small studies and high throughput datasets that implicate Aurora-A, particularly, in the pathogenesis of SCCHN. Early phase clinical trials are beginning to evaluate the activity of small molecule inhibitors of the Aurora kinases. We summarize the state of current trials evaluating Aurora inhibitors in SCCHN, and discuss rational directions for future drug combination trials and biomarkers for use with Aurora-inhibiting agents.

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“…Astsaturov et al went on to demonstrate that combining Aurora kinase inhibitors with EGFR inhibitors potently reduced tumor cell growth both in vitro and in xenograft analysis, and showed that this was accompanied by general reduction in SRC kinase activity (Astsaturov et al, 2010). Further extending analysis of this network, Ratushny et al have recently found that dual inhibition of Aurora and SRC kinases is effective in reducing the growth of multiple classes of tumor cell lines (Ratushny et al, 2011). Cumulatively, this work is compatible with the idea that disruption of multiple proteins existing in a network proximally anchored to EGFR may have effectiveness, and suggests concepts that could support the development of multiple Phase I trials.…”

Section: Conclusion and Future Perspectives: Moving Towards A Sysmentioning

confidence: 98%

Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer

Mehra¹,

Serebriiskii²,

Dunbrack³

et al. 2011

Drug Resistance Updates

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Agents targeting EGFR and related ErbB family proteins are valuable therapies for the treatment of many cancers. For some tumor types, including squamous cell carcinomas of the head and neck (SCCHN), antibodies targeting EGFR were the first protein-directed agents to show clinical benefit, and remain a standard component of clinical strategies for management of the disease. Nevertheless, many patients display either intrinsic or acquired resistance to these drugs; hence, major research goals are to better understand the underlying causes of resistance, and to develop new therapeutic strategies that boost the impact of EGFR/ErbB inhibitors. In this review, we first summarize current standard use of EGFR inhibitors in the context of SCCHN, and described new agents targeting EGFR currently moving through pre-clinical and clinical development. We then discuss how changes in other transmembrane receptors, including IGF1R, c-Met, and TGF-β, can confer resistance to EGFR-targeted inhibitors, and discuss new agents targeting these proteins. Moving downstream, we discuss critical EGFR-dependent effectors, including PLC-γ; PI3K and PTEN; SHC, GRB2, and RAS and the STAT proteins, as factors in resistance to EGFR-directed inhibitors and as alternative targets of therapeutic inhibition. We summarize alternative sources of resistance among cellular changes that target EGFR itself, through regulation of ligand availability, post-translational modification of EGFR, availability of EGFR partners for hetero-dimerization and control of EGFR intracellular trafficking for recycling versus degradation. Finally, we discuss new strategies to identify effective therapeutic combinations involving EGFR-targeted inhibitors, in the context of new system level data becoming available for analysis of individual tumors.

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Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death

Cited by 28 publications

References 50 publications

Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion

Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion

Aurora kinases in head and neck cancer

Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer

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