Reactivating p53 tumour suppressor function

Harrison, Charlotte

doi:10.1038/nrd3834

In Brief
Published: 31 August 2012

Anticancer drugs

Reactivating p53 tumour suppressor function

Charlotte Harrison

Nature Reviews Drug Discovery volume 11, page 674 (2012)Cite this article

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These two papers investigated indirectly restoring p53 tumour suppressor function as an anticancer strategy. Gembarska et al. showed that the p53 pathway is inactivated in ∼65% of human melanomas as a result of increased expression of MDM4 (a negative regulator of p53). Inhibition of the MDM4–p53 interaction — using a specific cell-permeable stabilized peptide — restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF^V600E oncogene. This suggests that because it improves p53 function, MDM4 inhibition could be useful in combination therapy for melanoma. Bywater et al. showed that in lymphoma, activation of p53 RNA can be achieved through inhibition of RNA polymerase I, an enzyme that increases transcription of ribosomal RNA genes in cancer. A small molecule inhibitor of RNA polymerase I (CX-5461) selectively killed B-lymphoma cells and reduced tumour burden in a mouse model, and induced apoptosis in human leukaemia and lymphoma cell lines. These effects were shown to be a result of nucleolar disruption and activation of p53-dependent apoptotic signalling. This suggests that inhibiting RNA polymerase I, which activates p53, is a potential strategy for the treatment of haematological malignancies.

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ORIGINAL RESEARCH PAPERS

Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012)
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Bywater, M. J. et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22, 51–65 (2012)
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