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

Oncogene volume 31, pages 1217–1227 (2012)Cite this article

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.

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References

  • Anand S, Penrhyn-Lowe S, Venkitaraman AR . (2003). AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3: 51–62.

    Article  CAS  Google Scholar 

  • Astsaturov I, Ratushny V, Sukhanova A, Einarson MB, Bagnyukova T, Zhou Y et al. (2010). Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci Signal 3: ra67.

    Article  Google Scholar 

  • Bagnyukova TV, Serebriiskii IG, Zhou Y, Hopper-Borge EA, Golemis EA, Astsaturov I . (2010). Chemotherapy and signaling: How can targeted therapies supercharge cytotoxic agents? Cancer Biol Ther 10: 839–853.

    Article  CAS  Google Scholar 

  • Bellacosa A, Godwin AK, Peri S, Devarajan K, Caretti E, Vanderveer L et al. (2010). Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations. Cancer Prev Res (Phila) 3: 48–61.

    Article  CAS  Google Scholar 

  • Ben-Zéev A, Raz A . (1981). Multinucleation and inhibition of cytokinesis in suspended cells: reversal upon reattachment to a substrate. Cell 26: 107–115.

    Article  Google Scholar 

  • Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B et al. (1998). A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. Embo J 17: 3052–3065.

    Article  CAS  Google Scholar 

  • Boss DS, Beijnen JH, Schellens JH . (2009). Clinical experience with aurora kinase inhibitors: a review. Oncologist 14: 780–793.

    Article  CAS  Google Scholar 

  • Brandsma D, van den Bent MJ . (2007). Molecular targeted therapies and chemotherapy in malignant gliomas. Curr Opin Oncol 19: 598–605.

    Article  CAS  Google Scholar 

  • Cao Y, Liu Q . (2007). Therapeutic targets of multiple angiogenic factors for the treatment of cancer and metastasis. Adv Cancer Res 97: 203–224.

    Article  CAS  Google Scholar 

  • Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK et al. (2005). Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 102: 11011–11016.

    Article  CAS  Google Scholar 

  • Chou TC, Talalay P . (1984). Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27–55.

    Article  CAS  Google Scholar 

  • Dadke D, Jarnik M, Pugacheva EN, Singh MK, Golemis EA . (2006). Deregulation of HEF1 impairs M-phase progression by disrupting the RhoA activation cycle. Mol Biol Cell 17: 1204–1217.

    Article  CAS  Google Scholar 

  • Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T et al. (2003). Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161: 267–280.

    Article  CAS  Google Scholar 

  • Dutertre S, Descamps S, Prigent C . (2002). On the role of aurora-A in centrosome function. Oncogene 21: 6175–6183.

    Article  CAS  Google Scholar 

  • Dyck HG, Hamilton TC, Godwin AK, Lynch HT, Maines-Bandiera S, Auersperg N . (1996). Autonomy of the epithelial phenotype in human ovarian surface epithelium: changes with neoplastic progression and with a family history of ovarian cancer. Int J Cancer 69: 429–436.

    Article  CAS  Google Scholar 

  • Fei F, Stoddart S, Groffen J, Heisterkamp N . (2010). Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias. Mol Cancer Ther 9: 1318–1327.

    Article  CAS  Google Scholar 

  • Fernandez-Miranda G, Trakala M, Martin J, Escobar B, Gonzalez A, Ghyselinck NB et al. (2011). Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development. Development. 138: 2661–2672.

    Article  CAS  Google Scholar 

  • Friedman A, Perrimon N . (2007). Genetic screening for signal transduction in the era of network biology. Cell 128: 225–231.

    Article  CAS  Google Scholar 

  • Frisch SM, Screaton RA . (2001). Anoikis mechanisms. Curr Opin Cell Biol 13: 555–562.

    Article  CAS  Google Scholar 

  • Gautschi O, Heighway J, Mack PC, Purnell PR, Lara Jr PN, Gandara DR . (2008). Aurora kinases as anticancer drug targets. Clin Cancer Res 14: 1639–1648.

    Article  CAS  Google Scholar 

  • Giet R, Petretti C, Prigent C . (2005). Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 15: 241–250.

    Article  CAS  Google Scholar 

  • Glover DM, Leibowitz MH, McLean DA, Parry H . (1995). Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81: 95–105.

    Article  CAS  Google Scholar 

  • Guan Z, Wang XR, Zhu XF, Huang XF, Xu J, Wang LH et al. (2007). Aurora-A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells. Cancer Res 67: 10436–10444.

    Article  CAS  Google Scholar 

  • Guarino M . (2010). Src signaling in cancer invasion. J Cell Physiol 223: 14–26.

    CAS  PubMed  Google Scholar 

  • Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL et al. (2008). Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22: 1200–1206.

    Article  CAS  Google Scholar 

  • Huang X, Dai W, Darzynkiewicz Z . (2005). Enforced adhesion of hematopoietic cells to culture dish induces endomitosis and polyploidy. Cell Cycle 4: 801–805.

    Article  CAS  Google Scholar 

  • Johnson FM, Saigal B, Talpaz M, Donato NJ . (2005). Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res 11: 6924–6932.

    Article  CAS  Google Scholar 

  • Jones RJ, Avizienyte E, Wyke AW, Owens DW, Brunton VG, Frame MC . (2002). Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. Br J Cancer 87: 1128–1135.

    Article  CAS  Google Scholar 

  • Kaestner P, Stolz A, Bastians H . (2009). Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells. Mol Cancer Ther 8: 2046–2056.

    Article  CAS  Google Scholar 

  • Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M et al. (2010). Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362: 2260–2270.

    Article  CAS  Google Scholar 

  • Kasahara K, Nakayama Y, Nakazato Y, Ikeda K, Kuga T, Yamaguchi N . (2007). Src signaling regulates completion of abscission in cytokinesis through ERK/MAPK activation at the midbody. J Biol Chem 282: 5327–5339.

    Article  CAS  Google Scholar 

  • Keen N, Taylor S . (2004). Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4: 927–936.

    Article  CAS  Google Scholar 

  • Kopetz S, Shah AN, Gallick GE . (2007). Src continues aging: current and future clinical directions. Clin Cancer Res 13: 7232–7236.

    Article  CAS  Google Scholar 

  • Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K et al. (2004). Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47: 6658–6661.

    Article  CAS  Google Scholar 

  • Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E et al. (2003). Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 278: 51786–51795.

    Article  CAS  Google Scholar 

  • Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C . (1996). Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta-1 integrin-mediated signaling in lymphocytes. J Exp Med 184: 1365–1375.

    Article  CAS  Google Scholar 

  • Mustelin T, Hunter T . (2002). Meeting at mitosis: cell cycle-specific regulation of c-Src by RPTPalpha. Sci STKE 2002: pe3.

    PubMed  Google Scholar 

  • Ng MM, Chang F, Burgess DR . (2005). Movement of membrane domains and requirement of membrane signaling molecules for cytokinesis. Dev Cell 9: 781–790.

    Article  CAS  Google Scholar 

  • O'Neill GM, Golemis EA . (2001). Proteolysis of the docking protein HEF1 and implications for focal adhesion dynamics. Mol Cell Biol 21: 5094–5108.

    Article  CAS  Google Scholar 

  • Obara Y, Labudda K, Dillon TJ, Stork PJ . (2004). PKA phosphorylation of Src mediates Rap1 activation in NGF and cAMP signaling in PC12 cells. J Cell Sci 117: 6085–6094.

    Article  CAS  Google Scholar 

  • Orly J, Sato G . (1979). Fibronectin mediates cytokinesis and growth of rat follicular cells in serum-free medium. Cell 17: 295–305.

    Article  CAS  Google Scholar 

  • Pfeiffer P, Qvortrup C, Eriksen JG . (2007). Current role of antibody therapy in patients with metastatic colorectal cancer. Oncogene 26: 3661–3678.

    Article  CAS  Google Scholar 

  • Plotnikova OV, Golemis EA . (2011). Aurora-A kinase activity influences calcium signaling in kidney cells. J Cell Biol 193: 1021–1032.

    Article  CAS  Google Scholar 

  • Plotnikova OV, Pugacheva EN, Dunbrack RL, Golemis EA . (2010). Rapid calcium-dependent activation of Aurora-A kinase. Nat Commun 1: 1–8.

    Article  Google Scholar 

  • Pugacheva EN, Golemis EA . (2005). The focal adhesion scaffolding protein HEF1 regulates activation of the Aurora-A and Nek2 kinases at the centrosome. Nat Cell Biol 7: 937–946.

    Article  CAS  Google Scholar 

  • Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA . (2007). HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129: 1351–1363.

    Article  CAS  Google Scholar 

  • Shor AC, Keschman EA, Lee FY, Muro-Cacho C, Letson GD, Trent JC et al. (2007). Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res 67: 2800–2808.

    Article  CAS  Google Scholar 

  • Soncini C, Carpinelli P, Gianellini L, Fancelli D, Vianello P, Rusconi L et al. (2006). PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity. Clin Cancer Res 12: 4080–4089.

    Article  CAS  Google Scholar 

  • Wong ST, Goodin S . (2009). Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy 29: 954–965.

    Article  CAS  Google Scholar 

  • Yeatman TJ . (2004). A renaissance for SRC. Nat Rev Cancer 4: 470–480.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Lisa Vanderveer for assistance with maintaining EOC cell lines; Carolyn Slater for isolating and producing the primary HOSE cultures; Christine Klimowicz for assistance with the drug synergy assays; and Ilya Serebriiskii for assistance with editing the figures. This work was supported by R01-CA63366 and R01-CA113342; DOD W81XWH-07-1-0676 from the Army Materiel Command; and Tobacco Settlement funding from the State of Pennsylvania (to EAG); R01-CA140323 and the Ovarian Cancer Research Fund (to AKG); Ovarian SPORE P50 CA083638 (Project 4, to EAG, AKG, and DCC); R01-GM86877, an appropriation from the Commonwealth of Pennsylvania, and the Greenberg Fund (to TJY); R01-CA136596 and R01-CA151374 (to DCC); R01-CA50633 (to LMW); and by NCI CA06927 and support from the Pew Charitable Fund (to Fox Chase Cancer Center). Additional funds were provided by Fox Chase Cancer Center via institutional support of the Head and Neck Cancer Keystone Program.

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  1. H B Pathak & A K Godwin

    Present address: Current address: University of Kansas Medical Center, Kansas City, KS 66106, USA.,

Authors and Affiliations

  1. Fox Chase Cancer Center, Philadelphia, PA, USA

    V Ratushny, H B Pathak, N Beeharry, N Tikhmyanova, F Xiao, T Li, S Litwin, D C Connolly, T J Yen, A K Godwin & E A Golemis

  2. Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA

    V Ratushny

  3. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    L M Weiner

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Ratushny, V., Pathak, H., Beeharry, N. et al. Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death. Oncogene 31, 1217–1227 (2012). https://doi.org/10.1038/onc.2011.314

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