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Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo

Oncogene volume 23, pages 3328–3337 (2004)Cite this article

Abstract

A single-nucleotide polymorphism (SNP) in exon 4 results in expression of either arginine (72R) or proline (72P) at codon 72 of p53. We demonstrate that the in vitro response of cells exposed to anticancer agents is strongly influenced by this SNP in wild-type p53. In inducible systems and in cells expressing the endogenous protein, expression of 72P wild-type p53 results in a predominant G1 arrest, with only a minor apoptosis, at drug concentrations causing extensive apoptosis in cells expressing the 72R wild-type variant. The superior apoptosis-inducing activity of the 72R form correlates with more efficient induction of specific apoptosis-associated genes, and is maximal in the presence of serine 46 (S46). In vivo, the outcome of chemo-radiotherapy of squamous carcinomas is more favourable in cancers retaining a wild-type 72R allele, such cases having higher response rates and longer survival than those with wild-type 72P. Together, these results reveal that this SNP is an important determinant of response to anticancer agents in cells expressing wild-type p53. Analysis of complete p53 genotype (mutation and SNP) merits detailed investigation as a simple means for prediction of treatment response and survival in clinical oncology.

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Acknowledgements

We thank Compagnia di San Paolo for supporting parts of this work.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Imperial College Faculty of Medicine, St Mary's Hospital, Norfolk Place, London, England

    Alexandra Sullivan, Nelofer Syed, Daniele Bergamaschi, Giuseppe Trigiante, Marlene Attard, Paul J Farrell, Paul Smith, Xin Lu & Tim Crook

  2. Department of Medical Oncology, S Croce e Carle Hospital, Cuneo, 12100, Italy

    Milena Gasco

  3. Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England

    Louise Hiller

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  1. Alexandra Sullivan
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  2. Nelofer Syed
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Correspondence to Tim Crook.

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Sullivan, A., Syed, N., Gasco, M. et al. Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo. Oncogene 23, 3328–3337 (2004). https://doi.org/10.1038/sj.onc.1207428

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