Abstract
Simple SummaryUterine Leiomyosarcoma (uLMS) is a rare (0.8 per 100,000 women), aggressive cancer that predominantly affects post-menopausal women. Prognosis for these women is poor, with relapse following primary treatment occurring in up to 70% of cases. For women with recurrent or advanced uLMS, there is no optimal therapeutic strategy, and research to develop novel, targeted therapies is needed. This study investigates novel combinations in uLMS preclinical models. We present encouraging results using MDM2 inhibitor-based combination treatments, including the WIP1 phosphatase inhibitor GSK2830371. These data suggest that women with uLMS could respond to such combination treatments; therefore, these should be investigated in clinical trials. As these agents do not bind to and interfere with DNA, they offer a non-genotoxic alternative to the cytotoxic chemotherapy currently used in the recurrent setting.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.
Highlights
One of the main challenges facing clinicians when treating women with recurrent/ advanced uLMS, is the limited evidence for guiding systemic treatment options beyond primary debulking surgery
This study presents novel results from investigations into the potential of GSK2830371, a WIP1 inhibitor; Venetoclax, a BCL2 inhibitor; and MIM1, an MCL-1 inhibitor, to potentiate the effects of MDM2 inhibitors RG7388 and HDM201 in p53WT uLMS cells
RG7388, HDM201 and Venetoclax were obtained from Selleckchem (Houston, TX, USA); GSK2830371 was purchased from SIGMA; and MIM1 BioTechne (Abingdon, UK)
Summary
One of the main challenges facing clinicians when treating women with recurrent/ advanced uLMS, is the limited evidence for guiding systemic treatment options beyond primary debulking surgery. BCL2, MCL-1 and BCL-XL, the main anti-apoptotic proteins, were identified as cellular oncogenes, as they are frequently found to be overexpressed in human cancers and prevent normal or protective cell death mechanisms; there is a focus on developing inhibitors that have a high affinity and relative specificity for one or more members of this protein family [27,28,29,30]. This study presents novel results from investigations into the potential of GSK2830371, a WIP1 inhibitor; Venetoclax, a BCL2 inhibitor; and MIM1, an MCL-1 inhibitor, to potentiate the effects of MDM2 inhibitors RG7388 and HDM201 in p53WT uLMS cells
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