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Molecularly targeted therapies for p53-mutant cancers

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Abstract

The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

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Acknowledgements

We would like to thank Sam Short for her assistance with this submission.

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Correspondence to Powel H. Brown.

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This work was funded by a Komen SAB grant (P.H.B.), a Breast Cancer Research Foundation grant (P.H.B.), a John Charles Cain Distinguished Chair Award (P.H.B.), a John F. and Julie Young Award (P.H.B.), and a Cancer Center Support Grant (5 P30 CA016672-38 P.H.B.).

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PH Brown is on the Scientific Advisory Board of Susan G. Komen for the Cure. All remaining authors declare no actual, potential, or perceived conflict of interest that would prejudice the impartiality of this article.

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Zhao, D., Tahaney, W.M., Mazumdar, A. et al. Molecularly targeted therapies for p53-mutant cancers. Cell. Mol. Life Sci. 74, 4171–4187 (2017). https://doi.org/10.1007/s00018-017-2575-0

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