Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations.

Xiangbing Meng,Shaikamjad Umesalma,Eric J Devor,Xinhao Wang,Dawn E Quelle,Kristina W Thiel,William H Thiel,Kimberly K Leslie,Jianling Bi,Yiyang Li,Yujun Li,Shujie Yang

doi:10.1155/2018/3810108

Xiangbing Meng, Shaikamjad Umesalma + Show 10 more

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https://doi.org/10.1155/2018/3810108

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Abstract

Mutations in the “guardian of the genome” TP53 predominate in solid tumors. In addition to loss of tumor suppressor activity, a specific subset of missense mutations confers additional oncogenic properties. These “gain-of-function” (GOF) mutations portend poor prognosis across cancer types regardless of treatment. Our objective in this study was to identify novel therapeutic opportunities to overcome the deleterious effects of GOF TP53 mutants. Using gynecologic cancer cell lines with known TP53 mutational status, we established that treatment with a proteasome inhibitor induced cell death in cells with two recurrent GOF TP53 mutations (R175H and R248Q), and addition of a histone deacetylase inhibitor (HDACi) enhanced this effect. By contrast, p53-null cancer cells were relatively resistant to the combination. Proteasome inhibition promoted apoptosis of cells with TP53 GOF mutations, potentially through induction of the unfolded protein response. In line with the reported hyperstabilization of GOF p53 protein, cells treated with HDACi exhibited reduced levels of p53 protein. Together, these data form the basis for future clinical studies examining therapeutic efficacy in a preselected patient population with GOF TP53 mutations.

Highlights

The Cancer Genome Atlas (TCGA) project has substantiated the long-held notion that the “guardian of the genome” TP53 is the most mutated gene in tumors [1]
In a recently published work, we evaluated the relationship of the eight GOF TP53 mutations with progression-free survival (PFS), risk of recurrence, and response to standard platinum and taxane chemotherapy in serous ovarian cancer [9]
We first examined the sensitivity of two well-characterized endometrial cancer cell lines with known p53 mutational status to the proteasome inhibitor, bortezomib (Velcade®)

Summary

Introduction

The Cancer Genome Atlas (TCGA) project has substantiated the long-held notion that the “guardian of the genome” TP53 is the most mutated gene in tumors [1]. While it is appreciated that TP53 mutations occur in a substantial number of tumors, it is critically important to note that varying types of p53 mutant proteins exist, with different implications for chemosensitivity. Other mutations are loss of function (LOF) or p53-null in which single amino acid changes completely inactivate or destabilize the protein. An interesting category is the gain-of-function (GOF) or “oncogenic” TP53 mutations that convert p53 from a tumor suppressor to an oncogene. The majority of LOF and GOF TP53 mutations result in loss of DNA binding to canonical p53 targets.

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