In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 9 ( 2018-02-27), p. 2198-2203
Abstract:
TP53 mutations occur in ∼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 that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53 R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1719001115
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2018
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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