title: Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy.
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.
authors.affiliation: Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.forename: James
authors.initials: J
authors.lastname: Rosinski
authors.forename: Zoran
authors.initials: Z
authors.lastname: Filipovic
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Holly
authors.initials: H
authors.lastname: Hilton
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhao
authors.forename: Binh T
authors.initials: BT
authors.lastname: Vu
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.forename: David C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2