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PNAS 103 (6): 1888-1893

Copyright © 2006 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy

Christian Tovar*,{dagger}, James Rosinski*,{dagger}, Zoran Filipovic*, Brian Higgins*, Kenneth Kolinsky*, Holly Hilton*, Xiaolan Zhao*, Binh T. Vu*, Weiguo Qing*, Kathryn Packman*, Ola Myklebost{ddagger}, David C. Heimbrook*, and Lyubomir T. Vassilev*,§

*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and {ddagger}Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, Norway

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved December 9, 2005

Received for publication August 28, 2005.

Abstract Back to Top

Abstract: The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53–MDM2 interaction.

Key Words: apoptosis • inhibitor • cell cycle • tumor • xenograft

Footnotes Back to Top

See Commentary on page 1659.

{dagger}C.T. and J.R. contributed equally to this work.

Author contributions: C.T., J.R., W.Q., K.P., and L.T.V. designed research; C.T., J.R., Z.F., B.H., K.K., H.H., X.Z., and L.T.V. performed research; B.T.V. and O.M. contributed new reagents/analytic tools; C.T., J.R., H.H., B.T.V., W.Q., K.P., O.M., D.C.H., and L.T.V. analyzed data; and O.M., D.C.H., and L.T.V. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

§To whom correspondence should be addressed. E-mail: lyubomir.vassilev{at}roche.com

© 2006 by The National Academy of Sciences of the USA

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