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Tipping growth inhibition into apoptosis by combining treatment with MDM2 and WIP1 inhibitors in p53WT uterine leiomyosarcoma

Lookup NU author(s): Victoria Chamberlain, Dr Yvette Drew, Professor John LunecORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 by the authors. Licensee MDPI, Basel, Switzerland. As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 inhibitors. Growth inhibition and cytotoxic assays were used to evaluate uLMS cell line responses to MDM2 inhibitors as single agents and in combination, qRT-PCR to assess transcriptional changes and Caspase-Glo 3/7 assay to detect apoptosis. RG7388 and HDM201 are potent, selective antagonists of the MDM2-p53 interaction that can effectively stabilise and activate p53 in a dose-dependent manner. GSK2830371, a potent and selective WIP1 phosphatase inhibitor, was shown to significantly potentiate the growth inhibitory effects of RG7388 and HDM201, and significantly increase the mRNA expression of p53 transcriptional target genes in a p53WT cell line at a concentration that has no growth inhibitory effects as a single agent. RG7388, HDM201 and GSK2830371 failed to induce apoptosis as single agents; however, a combination treatment tipped cells into apoptosis from senescence. These data present the possibility of MDM2 and WIP1 inhibitor combinations as a potential treatment option for p53WT uLMS patients that warrants further investigation.

Publication metadata

Author(s): Chamberlain V, Drew Y, Lunec J

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2022

Volume: 14

Issue: 1

Online publication date: 21/12/2021

Acceptance date: 16/12/2021

Date deposited: 10/01/2022

ISSN (electronic): 2072-6694

Publisher: MDPI


DOI: 10.3390/cancers14010014


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Funder referenceFunder name
SUK201.2017Sarcoma UK