title: p53 rescue through HDM2 antagonism suppresses melanoma growth and potentiates MEK inhibition.
abstract: Oncogenesis reflects an orchestrated interaction between misguided growth signals. Although much effort has been launched to pharmacologically disable activated oncogenes, one sidelined approach is the restoration of tumor suppressive signals. As TP53 is often structurally preserved, but functionally crippled, by CDKN2A/ARF loss in melanoma, rescue of p53 function represents an attractive point of vulnerability in melanoma. In this study, we showed that both p53 protein and activity levels in melanoma cells were strongly induced by nutlin-3, a canonical HDM2 antagonist. Among a test panel of 51 cell lines, there was a marked reduction in melanoma viability that was directly linked to TP53 status. Moreover, we also found that the melanoma growth suppression mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibition was potentiated by HDM2 antagonism. These results provide fundamental insights into the intact p53 circuitry, which can be restored through small molecule inhibitors and potentially deployed for therapeutic gain.
authors: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors: Zhenyu
authors: Z
authors: Ji
authors: Ching Ni
authors: CN
authors: Njauw
authors: Michael
authors: M
authors: Taylor
authors: Victor
authors: V
authors: Neel
authors: Keith T
authors: KT
authors: Flaherty
authors: Hensin
authors: H
authors: Tsao
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D002070:Butadienes; D007093:Imidazoles; D009570:Nitriles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C113580:U 0126; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases