Preprint Article Version 1 This version is not peer-reviewed

Novel Combinatorial Therapeutic Strategy to Overcome Gain-of-Function p53 Mutations

Version 1 : Received: 3 May 2018 / Approved: 4 May 2018 / Online: 4 May 2018 (09:03:27 CEST)

How to cite: Meng, X.; Yang, S.; Li, Y.; Li, Y.; Bi, J.; Wang, X.; Umesalma, S.; Devor, E.J.; Thiel, K.W.; Quelle, D.E.; Leslie, K.K. Novel Combinatorial Therapeutic Strategy to Overcome Gain-of-Function p53 Mutations. Preprints 2018, 2018050088 (doi: 10.20944/preprints201805.0088.v1). Meng, X.; Yang, S.; Li, Y.; Li, Y.; Bi, J.; Wang, X.; Umesalma, S.; Devor, E.J.; Thiel, K.W.; Quelle, D.E.; Leslie, K.K. Novel Combinatorial Therapeutic Strategy to Overcome Gain-of-Function p53 Mutations. Preprints 2018, 2018050088 (doi: 10.20944/preprints201805.0088.v1).

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. Towards understanding the mechanism, we found that proteasome inhibition promotes 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.

Subject Areas

p53; proteasome inhibitor; endometrial cancer; ovarian cancer; gain-of-function mutation

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