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- 2018
Selective targeting of p53 gain-of-function mutants in cancerKeywords: mutant p53, cancer, personalized therapeutics, p53, USP15 Abstract: Gain-of-function (GOF) mutations in p53 are frequent in many human cancers and play key roles in tumor progression and development of drug resistance [1] (Figure (Figure1).1). Unlike tumor suppressive wild-type (WT) p53 protein, which is rapidly turned over in cells by the ubiquitin proteasome system, the GOF mutants form stable aggregates that accumulate in cancer cells [1, 2] (Figure (Figure1).1). Depletion of mutant GOF p53 mutants in cancer cells has been shown to induce cancer cell death; demonstrating a key role for these mutants in cancer cell survival and tumor progression [3, 4]. While the therapeutic merits of strategies that can selectively deplete GOF mutant p53 proteins in cancer cells are well appreciated, achieving such selective depletion in a clinically translatable manner has been difficult. A major challenge in developing a clinically viable strategy to selectively target mutant p53 proteins in cancer has been the need to differentiate and exclude the tumor suppressive wild-type p53 protein present in the healthy cells from being targeted. Realizing this goal requires better understanding of upstream regulators and pathways that selectively regulate the different p53 GOF mutants in cells. Recently, the deubiquitinase USP15 was identified as a selective upstream regulator of the p53- R175H conformational mutant in ovarian cancer cells [3]. Depletion of USP15 in ovarian cancer cells causes decrease in p53-R175H protein levels and induces cell death in cancer cells expressing this mutant form of p53 [3]. Thus, targeting USP15 provides a new and selective way to deplete p53-R175H protein and achieve killing of cancer cells carrying this mutation. USP15 levels have been shown to be elevated in many cancers and several new evidences linking the role of this deubiquitinase to cancer progression is beginning to emerge [5]. In addition to identifying a selective druggable regulator of p53-R175H mutant, this discovery also established the existence of unique regulators of the different GOF p53 mutants. Identifying these regulators will open up new avenues to target the respective oncogenic mutations in cancer cells
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