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

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.

• Authors: V Ratushny, H B Pathak, N Beeharry, N Tikhmyanova, F Xiao, T Li, S Litwin, D C Connolly, T J Yen, L M Weiner, A K Godwin, E A Golemis
• Journal: Oncogene (Oncogene) Vol. 31 Issue 10 Pg. 1217-27 (Mar 08 2012) ISSN: 1476-5594 [Electronic] England
• PMID: 21785464 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• PHA 680632
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Pyrroles
• Thiazoles
• src-Family Kinases
• AURKA protein, human
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Dasatinib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase A
• Aurora Kinases
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Dasatinib
• Female
• Humans
• Mitosis (drug effects)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Thiazoles (pharmacology)
• src-Family Kinases (antagonists & inhibitors, physiology)