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

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. 12 independent biological samples were analyzed to compare tumors that were sensitive (n=8) or resistant (n=4) to genetic p53 restoration