Journal article
Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death
Oncogene, v 31(10), pp 1217-1227
01 Mar 2012
PMID: 21785464
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Increased activity of SRC family kinases promotes tumor invasion and metastasis, and overexpression of the mitotic regulator Aurora kinase A (AURKA) drives tumor aneuploidy and chromosomal instability. These functions nominate SRC and AURKA as valuable therapeutic targets for cancer, and inhibitors for SRC and Aurora kinases are now being used in the clinic. In this study, we demonstrate potent synergy between multiple inhibitors of Aurora and SRC kinases in ovarian and colorectal cancer cell lines, but not in normal ovarian epithelial cell lines. Combination of Aurora and SRC inhibitors selectively killed cells that have undergone a preceding aberrant mitosis, and was associated with a postmitotic reattachment defect, and selective removal of aneuploid cell populations. Combined inhibition of Aurora kinase and SRC potentiated dasatinib-dependent loss of activated (Y416-phosphorylated) SRC. SRC and AURKA share a common interaction partner, NEDD9, which serves as a scaffolding protein with activities in cell attachment and mitotic control, suggesting SRC and AURKA might interact directly. In vitro, we observed physical interaction and mutual cross-phosphorylation between SRC and AURKA that enhanced SRC kinase activity. Together, these findings suggest that combination of SRC and Aurora-targeting inhibitors in the clinic may be a productive strategy. Oncogene (2012) 31, 1217-1227; doi:10.1038/onc.2011.314; published online 25 July 2011
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Details
- Title
- Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death
- Creators
- V. Ratushny - Fox Chase Cancer CenterH. B. Pathak - University of Kansas Medical CenterN. Beeharry - Fox Chase Cancer CenterN. Tikhmyanova - Fox Chase Cancer CenterF. Xiao - Fox Chase Cancer CenterT. Li - Fox Chase Cancer CenterS. Litwin - Fox Chase Cancer CenterD. C. Connolly - Fox Chase Cancer CenterT. J. Yen - Fox Chase Cancer CenterL. M. Weiner - Georgetown University Medical CenterA. K. Godwin - University of Kansas Medical CenterE. A. Golemis - Fox Chase Cancer Center
- Publication Details
- Oncogene, v 31(10), pp 1217-1227
- Publisher
- Springer Nature
- Number of pages
- 11
- Grant note
- DOD W81XWH-07-1-0676 / Army Materiel Command; U.S. Army Medical Research & Materiel Command (USAMRMC) P50 CA083638 / Ovarian SPORE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Pew Charitable Fund R01CA050633 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Commonwealth of Pennsylvania Ovarian Cancer Research Fund CA06927 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Fox Chase Cancer Center Greenberg Fund R01GM086877 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) State of Pennsylvania
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Mechanical Engineering and Mechanics
- Web of Science ID
- WOS:000301344600002
- Scopus ID
- 2-s2.0-84858007264
- Other Identifier
- 991019167318504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Genetics & Heredity
- Oncology