title: A stapled p53 helix overcomes HDMX-mediated suppression of p53.
abstract: Cancer cells neutralize p53 by deletion, mutation, proteasomal degradation, or sequestration to achieve a pathologic survival advantage. Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels. However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53. Here, we report that a stapled p53 helix preferentially targets HDMX, blocks the formation of inhibitory p53-HDMX complexes, induces p53-dependent transcriptional upregulation, and thereby overcomes HDMX-mediated cancer resistance in vitro and in vivo. Importantly, our analysis of p53 interaction dynamics provides a blueprint for reactivating the p53 pathway in cancer by matching HDM2, HDMX, or dual inhibitors to the appropriate cellular context.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Bernal
authors.forename: Mark
authors.initials: M
authors.lastname: Wade
authors.forename: Marina
authors.initials: M
authors.lastname: Godes
authors.forename: Tina N
authors.initials: TN
authors.lastname: Davis
authors.forename: David G
authors.initials: DG
authors.lastname: Whitehead
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D015202:Protein Engineering; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2