Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

Frances K Turrell, Emma M Kerr, Meiling Gao, Hannah Thorpe, Gary J Doherty, Jake Cridge, David Shorthouse, Alyson Speed, Shamith Samarajiwa, Benjamin A Hall, Meryl Griffiths, Carla P Martins

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Abstract

Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine Kras G12D -p53 null , -p53 R172H (conformational), and -p53 R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53 R270H -specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant.

Original languageEnglish
Pages (from-to)1339-1353
Number of pages15
JournalGenes & development
Volume31
Issue number13
DOIs
Publication statusPublished - 08 Aug 2017

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    Turrell, F. K., Kerr, E. M., Gao, M., Thorpe, H., Doherty, G. J., Cridge, J., Shorthouse, D., Speed, A., Samarajiwa, S., Hall, B. A., Griffiths, M., & Martins, C. P. (2017). Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity. Genes & development, 31(13), 1339-1353. https://doi.org/10.1101/gad.298463.117