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Global gene expression profiling reveal distinct molecular profiles between p53-sensitive and p53-resistant T-cell lymphomas

ABSTRACT: TP53 mutations occur in approximately 50% of all human tumors with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant-p53 targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting it will unlikely be effective as a single therapy. The goal of the study was to identify the pathways conferring resistance or sensitivity to genetic p53 restoration in tumors with a p53 missense mutaiton Results:We sequenced the transcriptome of tumors that were sensitive or resistant to p53 restoration and found that TNF signaling was activated in p53-sensitive tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE109883 | GEO | 2018/05/01

REPOSITORIES: GEO

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Stage-specific sensitivity to p53 restoration in lung cancer: tumor data

Project description:Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations. 18 tumors of different grade and treatment status. 6 treated grade 3, 4 treated grade2, 4 untreated grade3, 4 untreated grade2

2010-11-24 | E-GEOD-23874 | biostudies-arrayexpress

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2010-11-24 | E-GEOD-23873 | biostudies-arrayexpress

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2010-11-24 | GSE23874 | GEO

Stage-specific sensitivity to p53 restoration in lung cancer: cell line data

2010-11-24 | GSE23873 | GEO