title: Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.
abstract: BACKGROUND
  Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients.
  
  
  METHODS
  PRIMA-1(Met), also known as APR-246, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. In this study, we interrogated the ability of APR-246 to induce apoptosis and inhibit tumour growth in ES cells with different p53 mutations.
  
  
  RESULTS
  APR-246 variably induced apoptosis, associated with Noxa, Puma or p21(WAF1) upregulation, in both mutant and wild-type p53 harbouring cells. The apoptosis-inducing capability of APR-246 was markedly reduced in ES cell lines transfected with p53 siRNA. Three ES cell lines established from the same patient at different stages of the disease and two cell lines of different patients with identical p53 mutations all exhibited different sensitivities to APR-246, indicating cellular context dependency. Comparative transcriptome analysis on the three cell lines established from the same patient identified differential expression levels of several TP53 and apoptosis-associated genes such as APOL6, PENK, PCDH7 and MST4 in the APR-246-sensitive cell line relative to the less APR-246-sensitive cell lines.
  
  
  CONCLUSIONS
  This is the first study reporting the biological response of Ewing sarcoma cells to APR-246 exposure and shows gross variability in responses. Our study also proposes candidate genes whose expression might be associated with ES cells' sensitivity to APR-246. With APR-246 currently in early-phase clinical trials, our findings call for caution in considering it as a potential adjuvant to conventional ES-specific chemotherapeutics.
authors.affiliation: 1] Children's Cancer Research Institute (CCRI), St Anna Kinderkrebsforschung, Zimmermannplatz 10, Vienna A-1090, Austria [2] Department of Pediatrics, Medical University, Vienna, Austria.
authors.forename: D N T
authors.initials: DN
authors.lastname: Aryee
authors.forename: S
authors.initials: S
authors.lastname: Niedan
authors.forename: J
authors.initials: J
authors.lastname: Ban
authors.forename: R
authors.initials: R
authors.lastname: Schwentner
authors.forename: K
authors.initials: K
authors.lastname: Muehlbacher
authors.forename: M
authors.initials: M
authors.lastname: Kauer
authors.forename: R
authors.initials: R
authors.lastname: Kofler
authors.forename: H
authors.initials: H
authors.lastname: Kovar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D046228:Microarray Analysis; D009154:Mutation / Q000502:physiology; D011812:Quinuclidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D011812:Quinuclidines; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C533410:eprenetapopt