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Ratushny V , Pathak HB , Beeharry N , Tikhmyanova N , Xiao F , Li T , Litwin S , Connolly DC , Yen TJ , Weiner LM , Godwin AK , Golemis EA
Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death
Oncogene. 2012 Mar 8;31(10) :1217-27
PMID: 21785464    PMCID: PMC3204164   
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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 (Y(416)-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.
Notes
Ratushny, V Pathak, H B Beeharry, N Tikhmyanova, N Xiao, F Li, T Litwin, S Connolly, D C Yen, T J Weiner, L M Godwin, A K Golemis, E A CA06927/CA/NCI NIH HHS/United States P30 CA006927-47/CA/NCI NIH HHS/United States P50 CA083638/CA/NCI NIH HHS/United States P50 CA083638-13/CA/NCI NIH HHS/United States R01 CA050633-22/CA/NCI NIH HHS/United States R01 CA063366-06/CA/NCI NIH HHS/United States R01 CA063366-17/CA/NCI NIH HHS/United States R01 CA113342-05/CA/NCI NIH HHS/United States R01 CA136596-04/CA/NCI NIH HHS/United States R01 CA140323-03/CA/NCI NIH HHS/United States R01 GM086877-07/GM/NIGMS NIH HHS/United States R01-CA113342/CA/NCI NIH HHS/United States R01-CA136596/CA/NCI NIH HHS/United States R01-CA140323/CA/NCI NIH HHS/United States R01-CA151374/CA/NCI NIH HHS/United States R01-CA50633/CA/NCI NIH HHS/United States R01-CA63366/CA/NCI NIH HHS/United States R01-GM86877/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Oncogene Oncogene. 2012 Mar 8;31(10):1217-27. doi: 10.1038/onc.2011.314. Epub 2011 Jul 25.