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Genes Dev. 2017 Jul 1;31(13):1339-1353. doi: 10.1101/gad.298463.117. Epub 2017 Aug 8.

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

Author information

1
Medical Research Council (MRC) Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, United Kingdom.
2
Department of Oncology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
3
Department of Histopathology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, CB2 0QQ, United Kingdom.

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 KrasG12D -p53null , -p53R172H (conformational), and -p53R270H (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 p53R270H -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

PMID:
28790158
PMCID:
PMC5580655
DOI:
10.1101/gad.298463.117
[Indexed for MEDLINE]
Free PMC Article

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