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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\n                    <jats:italic>mdm2<\/jats:italic>\n                    gene amplification were most sensitive to nutlin-3\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , 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\u2013MDM2 interaction.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0507493103","type":"journal-article","created":{"date-parts":[[2006,1,27]],"date-time":"2006-01-27T20:32:57Z","timestamp":1138393977000},"page":"1888-1893","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":593,"title":["Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy"],"prefix":"10.1073","volume":"103","author":[{"given":"Christian","family":"Tovar","sequence":"first","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"James","family":"Rosinski","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Zoran","family":"Filipovic","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Brian","family":"Higgins","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Kenneth","family":"Kolinsky","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Holly","family":"Hilton","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Xiaolan","family":"Zhao","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Binh T.","family":"Vu","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Weiguo","family":"Qing","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Kathryn","family":"Packman","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Ola","family":"Myklebost","sequence":"additional","affiliation":[{"name":"Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, Norway"}]},{"given":"David C.","family":"Heimbrook","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]},{"given":"Lyubomir T.","family":"Vassilev","sequence":"additional","affiliation":[{"name":"*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and"}]}],"member":"341","published-online":{"date-parts":[[2006,1,27]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81871-1"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/35042675"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208615"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1905840"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60785-X"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.950151008"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6690312"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s000180050273"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc991"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(97)01480-4"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90644-R"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092472"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(99)00487-4"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203012"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1044-579X(02)00099-8"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568009053332627"},{"key":"e_1_3_3_17_2","first-page":"7","volume":"120","author":"Vousden K. 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