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Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.

D N T Aryee1, S Niedan, J Ban

  • 11] Children's Cancer Research Institute (CCRI), St Anna Kinderkrebsforschung, Zimmermannplatz 10, Vienna A-1090, Austria [2] Department of Pediatrics, Medical University, Vienna, Austria.

British Journal of Cancer
|October 17, 2013
PubMed
Summary
This summary is machine-generated.

APR-246 shows variable effectiveness in treating Ewing sarcoma (ES) cells with mutant p53, highlighting the need for caution in its clinical application for this cancer. Further research is needed to understand the cellular context dependency of APR-246 response in ES.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mutations in p53 are rare in Ewing sarcoma (ES) but associated with poor prognosis.
  • Novel therapeutic strategies targeting mutant p53 ES are needed.
  • APR-246 (PRIMA-1(Met)) restores p53 function and induces cell death in various cancers.

Purpose of the Study:

  • To investigate the efficacy of APR-246 in inducing apoptosis and inhibiting tumor growth in ES cells with diverse p53 mutations.
  • To explore the role of p53 in APR-246's anti-cancer effects in ES.

Main Methods:

  • Treatment of ES cell lines with varying p53 mutation statuses using APR-246.
  • Assessment of apoptosis induction and cell growth inhibition.
  • RNA interference (siRNA) to deplete p53.
  • Comparative transcriptome analysis of ES cell lines with differential APR-246 sensitivity.

Main Results:

  • APR-246 induced apoptosis in ES cells, with varying responses observed across different cell lines and p53 mutation statuses.
  • Apoptosis induction was associated with upregulation of Noxa, Puma, or p21(WAF1).
  • APR-246's efficacy was reduced in p53-depleted cells, confirming p53's role.
  • Significant variability in APR-246 sensitivity was noted, dependent on cellular context and patient origin.
  • Differential gene expression, including TP53 and apoptosis-associated genes (APOL6, PENK, PCDH7, MST4), was identified in sensitive vs. less sensitive cell lines.

Conclusions:

  • This is the first study to report on the biological response of Ewing sarcoma cells to APR-246, revealing significant variability.
  • Candidate genes potentially influencing ES cell sensitivity to APR-246 were proposed.
  • Findings suggest caution regarding APR-246's use as an adjuvant therapy in ES, despite ongoing clinical trials.