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

Tovar, Christian, Rosinski, James, Filipovic, Zoran, Higgins, Brian, Kolinsky, Kenneth, Hilton, Holly, Zhao, Xiaolan, Vu, Binh T., Qing, Weiguo, Packman, Kathryn, Myklebost, Ola, Heimbrook, David C., Vassilev, Lyubomir T.·2006·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0507493103

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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.

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Authors: Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., Myklebost, O., Heimbrook, D. C., & Vassilev, L. T.
Affiliations: *Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and
F. Hoffmann-La Roche AG (CH)
Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, Norway
ORCID: Higgins, Brian
Zhao, Xiaolan
Vu, Binh T.
Packman, Kathryn
Myklebost, Ola
Vassilev, Lyubomir T.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2006-01-27
Volume: 103
Issue: 6
Pages: 1888-1893
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0507493103
OpenAlex: W1993263392
Cited by: 708
References: 36
Citations by year: 2026: 17 · 2025: 24 · 2024: 15 · 2023: 39 · 2022: 23 · 2021: 27 · 2020: 25 · 2019: 33 · 2018: 20 · 2017: 27 · 2016: 44 · 2015: 39 · 2014: 45 · 2013: 39 · 2012: 47
FWCI: 25.66
Type: journal article
Language: en
Open access: closed
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: MDM2 inhibitors, Nutlin-3, p53 pathway, p53-dependent apoptosis, cell cycle arrest, MDM2 amplification, p53-MDM2 interaction, apoptosis-related gene expression, cancer therapy
MeSH terms: Animals, Antineoplastic Agents, Cell Cycle, Cell Line, Humans, Imidazoles, Mice, Nude, Neoplasms, Piperazines, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Gene Expression Profiling, Xenograft Model Antitumor Assays, Mice, Proto-Oncogene Proteins c-mdm2

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

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