Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity
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Authors
Turrell, FK
Kerr, EM
Gao, M
Thorpe, H
Cridge, J
Speed, A
Griffiths, M
Pedro Martins, Carla
Publication Date
2017-08-08Journal Title
Genes and Development
ISSN
0890-9369
Publisher
Cold Spring Harbor Laboratory Press
Volume
31
Pages
1339-1353
Language
English
Type
Article
This Version
VoR
Metadata
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Turrell, F., Kerr, E., Gao, M., Thorpe, H., Doherty, G., Cridge, J., Shorthouse, D., et al. (2017). Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity. Genes and Development, 31 1339-1353. https://doi.org/10.1101/gad.298463.117
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.
Keywords
lung tumors, mevalonate pathway, mutant p53, p53 restoration, therapy, transcriptome analysis
Sponsorship
This work was supported by the Medical Research Council.
Funder references
MRC (MC_UU_12022/1_do not transfer?)
Medical Research Council (MC_UU_12022/9)
MRC ()
Royal Society (Paul Instrument Fund) (UF130039)
Medical Research Council (MC_UU_12022/4)
Cancer Research UK (CB4160)
MRC (MC_UU_12022/10)
Identifiers
External DOI: https://doi.org/10.1101/gad.298463.117
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267373
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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